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CAS No. : | 5961-59-1 | MDL No. : | MFCD00008399 |
Formula : | C8H11NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JFXDIXYFXDOZIT-UHFFFAOYSA-N |
M.W : | 137.18 | Pubchem ID : | 22250 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 42.24 |
TPSA : | 21.26 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.26 cm/s |
Log Po/w (iLOGP) : | 1.93 |
Log Po/w (XLOGP3) : | 1.24 |
Log Po/w (WLOGP) : | 1.55 |
Log Po/w (MLOGP) : | 1.48 |
Log Po/w (SILICOS-IT) : | 1.5 |
Consensus Log Po/w : | 1.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.78 |
Solubility : | 2.26 mg/ml ; 0.0165 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.28 |
Solubility : | 7.13 mg/ml ; 0.052 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.93 |
Solubility : | 0.16 mg/ml ; 0.00116 mol/l |
Class : | Soluble |
PAINS : | 1.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P272-P280-P301+P312+P330-P302+P352-P305+P351+P338-P333+P313-P337+P313-P501 | UN#: | N/A |
Hazard Statements: | H302-H317-H320 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium bis(2-methoxyethoxy)aluminium dihydride In toluene for 0.166667h; | |
With lithium borohydride | ||
With lithium aluminium tetrahydride |
With dimethylsulfide borane complex In tetrahydrofuran for 3h; Heating; Yield given; | ||
Multi-step reaction with 2 steps 1: anhydrous potassium carbonate, sodium hydroxide, tetrabutylammonium hydrogensulphate / benzene / 1 h / 5 - 10 °C / Heating 2: water / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With butyl triphenylphosphonium tetraborate at 20℃; for 0.183333h; | |
94.2% | With 3 weight% Pd/C; hydrogen In methanol at 80℃; Autoclave; | 10; 12-15 Example 14 General procedure: A prepared autoclave with a capacity of 400 cm3 was charged with 5 g of Raney nickel and 100 ml of methanol, which corresponds to 10 wt. % of the pair-anisidine load. The autoclave loading nozzle was closed with a mixing cap. In one of the burettes there was poured 40.87 g of formalin containing 29.8 wt. % formaldehyde, which corresponds to the mass of 18.2% of the free working volume of the reactor, to another solution 50 g of para-anisidine in 80 ml of methanol, which corresponds to 59 wt. % of the free working volume of the reactor and the concentration of para-anisidine in a solution of 44.1 wt. % (17 mol. %), asked the flow rates of raw materials, based on the calculation of the full, simultaneous emptying of burettes for 1 hour. Automatic tracking system for the flow ratio was switched on, the pump was switched on. After the full filling of PTFE tubes, the pump was turned off and these tubes were connected to the mixer. (0036) The autoclave was sealed and purged with nitrogen to remove air from it and then with hydrogen for nitrogen displacement, creating hydrogen pressure of 5 atm, the temperature was set to +80° C. and included a thermostat. Upon reaching the set temperature in the autoclave, the stirrer drive and the micropump were switched on. Formalin and the para-anisidine solution were pumped from burettes to the mixer, where the streams were mixed and para-anisidine reacted with formaldehyde to form a water-methanol solution of Schiff base (azomethine)-4-methoxy-(N-phenylmethanimine). The resulting solution of 4-methoxy-(N-phenylmethanimine) with a molar ratio of components Schiff base:methanol:water=1:4.88:4.92 in the form of droplets came from the mixer to a suspension of Raney nickel in methanol, where it was rapidly hydrogenated to form a secondary amine. The flow rate control in the flows was carried out with the help of burettes, by decreasing the liquid level for certain periods of time. (0037) After the reagents were completely exhausted from the burettes (approximately 1 hour), the pump was turned off, the shutter speed was given for 0.5 hours, after which the heating of the autoclave and the stirrer were turned off. The autoclave was cooled to +35° C., the catalyst was discharged through the bottom and cartridge filter into the receiving tank. (0038) Methanol, water and low-boiling impurities were distilled off from the obtained catalyzate at atmospheric pressure, the remaining mass was distilled off at a residual pressure of 20 mm Hg (0039) Received 53.48 g of the product of the composition: N-methyl-para-anisidine-75.44%, N, N-dimethyl-para-anisidine-17.85%, para-anisidine-6.7%. (0040) The output of N-methyl-para-anisidine-72.44%A method for producing N-methyl-para-anisidine of example 14 corresponds to example 12, except that 3 wt. % palladium on coal was used. There was received 55.5 g of the product composition: N-methyl-para-anisidine-94.5%, N, N-dimethyl-para-anisidine-1.9%, para-anisidine-3.6%. The yield of N-methyl-para-anisidine was 94.2%. |
80% | Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol for 1.75h; Heating; |
76% | With hydrogen In tetrahydrofuran at 120℃; for 9h; Autoclave; | |
75% | Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 6h; Stage #2: With methanol; sodium tetrahydroborate for 12h; Reflux; | |
72% | Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 50℃; for 5h; Inert atmosphere; Stage #2: With methanol; sodium tetrahydroborate at 20℃; Inert atmosphere; | |
65% | With sodium tetrahydroborate; sodium methylate In methanol 1) room temp., 5 h, 2) reflux; | |
61% | Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol for 2h; Reflux; | |
Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Inert atmosphere; Stage #2: With sodium tetrahydroborate In methanol Reflux; | ||
Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol for 1.75h; Reflux; | ||
Stage #1: formaldehyd; 4-methoxy-aniline With methanol; sodium methylate for 4h; Inert atmosphere; Reflux; Stage #2: With sodium tetrahydroborate at 0℃; for 2h; Reflux; Inert atmosphere; | ||
Stage #1: formaldehyd; 4-methoxy-aniline With sodium In methanol Stage #2: With sodium tetrahydroborate In methanol at 60℃; | ||
Stage #1: formaldehyd; 4-methoxy-aniline With acetic acid In ethanol at 20 - 25℃; for 3h; Stage #2: With sodium tetrahydroborate In ethanol | 2.2.1 Chemical synthesis of AQ-4 The commercially available compound, 4-methoxyaniline 1 (10 mmol,1.23 g) was dissolved in 20 ml anhydrous ethanol. Thereafter, paraformaldehyde (10 mmol, 0.90 g) and a drop of acetic acid as the catalyst were added to the mixture. After stirring at room temperature (20-25 °C) for 3 h, NaBH4 (10 mmol, 0.63 g) was added and the reaction was monitored using thin layer chromatography (TLC). When the reaction was completed, the resulting mixture was saturated with sodium carbohydrate and concentrated under a vacuum to afford intermediate 2 without further purification. The commercially-available compound, methyl 2-aminobenzoate 3 (5 mmol, 0.75 g), was dissolved in 40 ml of 1,4-dioxane; CD3CN (10 mmol, 0.44 g) was then added. The mixture continuously pumped HCl gas for 15 min and the reaction was refluxed and monitored with TLC. When the reaction reached its endpoint, the mixture was cooled and filtered to obtain a white solid, which was subsequently dissolved in water; K2CO3 solution was added to adjust the pH to 9. Under this condition, a large amount of white precipitate could be obtained as intermediate 4. Intermediate 4 (5 mmol, 0.81 g) was then dissolved in 50 ml of toluene, and added to N,N-diisopropylethylamine (DIPEA, 7.5 mmol, 0.97 g). After the mixture was refluxed for 2 h, POCl3 (7.5 mmol, 1.15 g) was slowly added dropwise at 80 °C. After the reaction was completed, the pH of the mixture was adjusted to 9 with K2CO3 solution, and the solution was extracted with ethyl acetate (EtOAc) to obtain intermediate 5. Finally, the last step was performed using intermediates 2 and 5. Intermediate 5 (5 mmol, 0.903 g) was slowly added to a solution of 2 (5 mmol, 0.685 g) in 50 ml of isopropanol. After reacting at room temperature for 8-10 h, isopropanol was removed under a vacuum. The pH of the reaction system was adjusted to 9 with NaHCO3 and then extracted with EtOAc. The organic phase was concentrated to obtain the crude product and then purified by column chromatography (EtOAc: petroleum ether = 20:1-3:1) to afford the target compound, AQ-4. | |
Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Stage #2: With methanol; sodium tetrahydroborate at 0℃; for 1.75h; Reflux; | C. General procedure for the methylation of anilines General procedure: A solution of NaOMe in MeOH (100 mmol, 20 mL) was added to a suspension of aniline (20 mmol), paraformaldehyde (28 mmol, 0.841 g) and MeOH (30 mL). The mixture was stirred for 5 h at room temperature. NaBH4 (20 mmol, 0.757) was added stepwise at 0 °C, and the mixture was then stirred for 1.7 h under reflux. The solvent was removed under reduced pressure, and a solution of KOH (1 M, 50 mL) was added. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. N-methylanilines were used in the next step without further purification. | |
Stage #1: formaldehyd; 4-methoxy-aniline With sodium methylate In methanol at 20℃; for 5h; Stage #2: With sodium tetrahydroborate In methanol for 1.75h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 25℃; | ||
In acetonitrile at 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine; In dichloromethane; at 0 - 20℃; for 20h; | General procedure: To a stirred solution of the aniline 7 and triethylamine (1 equiv)in CH2Cl2 (~0.9 mM) at 0 C was added acid bromide 8 (1 equiv) in CH2Cl2 (~0.6 M) via cannula. The solution was allowed to warm to rt and stirred for 20 h. Further CH2Cl2 was added and the organics washed with 10% HCl solution, brine, dried (MgSO4) and concentrated in vacuo to afford the title compounds 9a-i which could be used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol at 20℃; for 8h; | 1.b (2-CHLORO-QUINAZOLIN-4-YL)- (4-METHOXY-PHENYL)-METHYL-AMINE : A solution of 2,4-dichloroquinazoline (300 mg, 1.51 mmol) and 4-methoxy-N-methylaniline (248 mg, 1.81 mmol) in 5 ml isopropanol with a drop of concentrated HCI was stirred at room temperature for 8 h. White precipitates were observed in the reaction mixture. The reaction was filtered, and the solid was washed with isopropanol, and dried under vacuum to give white powder (260 mg, 87%). 1H NMR (CDC13) : 8.66 (dd, J= 8.4 and 0.9 Hz, 1H), 7.75 (ddd, J = 8. 1,7. 5 and 0.9 Hz, 1H), 7.26-7. 19 (M, 3H), 7.14 (ddd, J= 8. 1,7. 5,0. 9 Hz, 1H), 7.06 (dd, J= 6.9 and 2.4 Hz, 2H), 6.75 (D, J = 8. 7 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H). |
87% | With hydrogenchloride In isopropyl alcohol at 20℃; for 8h; | 1.b 2,4-dichloroquinazoline (300 mg, 1.51 mmol) and 4-methoxy-N-methylaniline (248 mg, 1.81 mmol) in 5 ml isopropanol with a drop of concentrated HCl was stirred at room temperature for 8 h. White precipitates were observed in the reaction mixture. The reaction was filtered, and the solid was washed with isopropanol, and dried under vacuum to give white powder (260 mg, 87%). 1H NMR (CDCl3): 8.66 (dd, J= 8.4 and 0.9 Hz, IH), 7.75 (ddd, J = 8.1, 7.5 and 0.9 Hz, IH), 7.26-7.19 (m, 3H), 7.14 (ddd, J= 8.1, 7.5, 0.9 Hz, IH), 7.06 (dd, J= 6.9 and 2.4 Hz, 2H), 6.75 (d, J= 8.7 Hz, IH), 3.91 (s, 3H), 3.81 (s, 3H). |
87% | With hydrogenchloride In water; isopropyl alcohol at 20℃; for 8h; |
81.3% | With triethylamine In tetrahydrofuran at 20℃; | 4.1.4. Synthesis of intermediate 18 To a solution of 17 (3.2 g, 0.016 mol) in 50 mL THF was added Et3N(3.3 mL, 0.024 mol) and N-methyl-4-methoxyaniline (1.9 g, 0.014 mol),and the mixture was stirred at room temperature overnight. The mixturewas extracted with CH2Cl2 (3×50 mL). The combined organiclayers were then washed with brine, dried over anhydrous Na2SO4, andconcentrated in vacuo. The residue was then purified by flash columnchromatography using PE/EA 15:1 as the fluent to afford 18 (3.9 g,81.3%) as white powder. 1H NMR (300 MHz, CDCl3) δ 7.64 (d,J=8.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.89(m, 4H), 3.78 (s, 3H), 3.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.54,158.68, 156.56, 152.98, 139.94, 132.57, 127.65, 127.49, 126.38,124.93, 115.44, 114.78, 55.56, 43.26; ESI-MS m/z 299.1 [M+H]+300.1. |
9% | In isopropyl alcohol at 20℃; for 12h; | 6.6. General method for the synthesis of compounds 1-10 General procedure: To a 100 mL round-bottomed flask substituted-4-chloroquinazolines(1 equivalent), appropriate anilines (1.2 equivalents) and isopropanol(10 mL) were added and stirred at room temperature for 12 h. Thecompounds precipitated as HCl salts, which were filtered and dried invacuo over P2O5 to afford the desired compounds. |
With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 0.5h; | 5.1 To a solution of 2,4-dichloroquinazoline (100 mg, 0.502 mmol) in DMF (2.5 mL) were added 4-methoxy-N-methylaniline (68.9 mg, 0.502 mmol) and sodium hydroxide (20.1 mg, 0.502 mmol), and the mixture was stirred for 0.5 h at RT. The reaction mixture was diluted with AcOEt, washed successively with water and brine, and dried over Na2SO4. The organic layer was concentrated in vacuo. The resultant residue was used for the next step without further purification. LCMS(m/z) 300.08 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With sodium acetate; In tetrahydrofuran; at 20℃; for 96h; | A mixture of (4-methoxy-phenyl)-methyl-amine (860 mg, 6.3 mmol), NaOAc (1.52 g, 18.5 mmol), THF (34 mL), H2O (24 mL) and the <strong>[39576-82-4]2,4-dichloro-6-methyl-quinazoline</strong> prepared above was stirred at room temperature for 4 days. Volatile organics were then removed and the resulting solid collected via vacuum filtration. Purification by gradient MPLC (SiO2, 0 to 50%, EtOAc/hexanes) provided the title compound as a white solid (874 mg; 44%). 1H NMR (CDCl3) delta 7.63 (d, 1H), 7.39 (dd, 1H), 7.05-7.18 (m, 2H), 6.92-6.98 (m, 2H), 6.62-6.66 (m, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 2.09 (s, 3H). |
In isopropyl alcohol; at 20℃; | (2-CHLORO-6-METHYL-QUINAZOLIN-4-YL)- (4-METHOXY-PHENYL)-METHYL-AMINE : The above 6-methyl-quinazoline-2,4-dione (201 mg, 1.14 mmol) and N, N- dimethylaniline (0.2 mL) were refluxed in phosphorus oxychloride (5 mL) under argon overnight. The solvent was removed by distillation under reduced pressure. The purple residue was dissolved in isopropanol (10 mL). N-METHYL-P-ANISIDINE (201 mg, 1.465 mmol) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (SI02, EtOAc: hexanes 5-25%) to give the product as a light yellow solid (62 mg, 17 %) : H NMR (CDCI3) 7.62 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 1. 8,8. 7 Hz, 1H), 7.16- 7.10 (M, 2H), 6.89-6. 86 (M, 2H), 6.63 (s, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 2.09 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; for 1.5h;Heating / reflux; | A solution of l,4-dichloro-5-fluorophthalazine (79.5 mg, 0.44 mmol) and N- methyl-p-anisidine (78.0 mg, 0.57 mmol) in /-PrOH (3 mL) was heated to reflux for 1.5 h. The reaction mixture was cooled to rt and then concentrated onto a mixture of SiO2 and Na2CO3. The reaction mixture was purified by two gradient MPLC columns (SiO2, 0 to 100 %, EtOAc/hexanes, 30 min; then SiO2, 0 to 30 %, EtOAc/hexanes, 30 min.) to EPO <DP n="57"/>provide 14.5 mg (15 %) of the title compounds as a 2:1 mixture. Major Isomer: 1H NMR (DMSO-J6) delta 7.98 - 8.04 (m, 1 H), 7.77 (td, 1 H), 7.24 (ddd, 1 H), 6.85 - 6.91 (m, 2 H), 6.73 - 6.79 (m, 2 H), 3.76 (s, 3 H), 3.59 (s, 3 H). MS (ES) 318 (M + H). Minor Isomer: 1H NMR (DMSO-J6) delta 7.44 (td, 0.5 H), ,7.32 - 7.44 (m, 1 H), 6.97 - 7.04 (m, 1 H), 6.80 - 6.87 (m, 1 H), 3.79 (s, 1.5 H), 3.58 (s, 1.5 H). MS (ES) 318 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With hydrogenchloride; In water; isopropyl alcohol; at 20 - 80℃; for 1.0h; | To an oven-dried one-neck reaction flask charged with a magnetic stir bar at rt under argon was added 4-chloro-2-methylthieno[2,3-fi(|pyrimidine (1.54 g, 8.34 mmol), isopropanol (40 mL), N-methyl-jo-anisidine (1.26 g, 9.17 mmol) and concentrated HCl (10 drops). The black solution was heated at 80C for 1 h and then cooled to rt. The precipitate was filtered and dried to give 0.860 g (36%) of the title compound as a yellow solid. 1H NuMR (DMSO-</6) 7.26-7.23 (m, 2H), 7.08-7.05 (m, 2H), 7.01 (d, J = 6.0 Hz, IH), 5.47 (d, J= 6.0 Hz, IH), 3.92 (s, 3H), 3.72 (s, 3H)7 2.91 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-acetyl-benzoic acid; N-methyl-N-(4-methoxyphenyl)amine With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 22h; Stage #2: With bicarbonate In dichloromethane; water | 4-Acetyl-N-(4-methoxy-phenyI)-N-methyl-benzamide 152. To a stirred solution of 4-acetylbenzoic acid (0.164 g, 1 mmol) and N-methyl-j?-anisidine (0.165 g, 1.2 mmol) in dry DCM (5 mL) and NEt3 (0.17 mL) was added DMAP (catalytic) and the solution was cooled on ice. To this was then added EDCI (0.383 g, 2 mmol) and the reaction was allowed to warm to rt with stirring over 22 h. To this was added sat. aq. bicarb, and DCM and the organic layer was separated and concentrated under reduced pressure. Purification by flash chromatography using an elution gradient of hexane to 30% EtOAc in hexane gave the title compound, 0.186 g5 66 %: 1H NMR δ (400 MHz, CDCl3) 2.47 (3H5 s), 3.40 (3H, s), 3.66 (3H5 s), 6.67 (2H5 d, J= 8.6 Hz), 6.89 (2H, d, J= 8.2 Hz)5 7.31 (2H, d5 J= 7.8 Hz)5 7.69 (2H5 d5 J= 7.8 Hz); 13C NMR δ (100 MHz, CDCl3) 26.5, 38.2, 55.2, 114.3, 127.5, 127.9, 128.5, 136.9, 137.0, 140.4, 158.0, 169.5, 197.4; LC/MS (APCI) m/z 304.47 (M-H)-; HPLC tT = 3.61 min (>99%) 90% MeCN m H2O. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In isopropyl alcohol; at 20℃; | General procedure: To a solution of 2,4-Dichloropyrimidine (1) (0.149g, 1.0 mmol) in 15 mL isopropanol was added 4-methoxy-N-methylaniline derivative (2) (1.0 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. When the reaction was completed, the solvent was removed under vacuum and the slurry was dilute with water (10 mL). The solution was adjusted to pH 9 with a saturated NaHCO3 solution, extracted with ethyl acetate (10 mL×3) for three times, the organic phase was washed with water (10 mL), dried over sodium sulfate, concentrated and purified by column chromatography to give the target compound 3a-3b. |
21% | EXAMPLE 11; (2,6-dimethyl-pyrimidin-4-yl)-(4-methyoxyphenyl)-methylamine.; [00108] To a stirring solution of <strong>[4472-45-1]4-chloro-2,6-dimethyl-pyrimidine</strong> (7 mmol, Ig), (4-methoxy-phenyl)-methyl-amine (7 mmol, 960mg), and isopropanol (35mL) was added concentrated HCl (4mL). Stirred at room temperature overnight. Evaporated the isopropanol, added aq. Na2Ctheta3, and extracted with dichloromethane. Dried the organic layer and concentrated. Chromatographed in 0 to 100% Ethyl Acetate in Hexanes to give 365 mg (21% yield). 1H NMR (400MHz) delta (ppm); 7.14 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 3.85(s, 3H), 3.44 (s, 3H), 2.55 (s, 3H), 2.19 (s, Hz, 3H). LC/MS; 244.31 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | EXAMPLE 2; Methyl 2-chloro-6-[(4-methoxyphenyl)(methyl)amino]pyrimidine-4-carboxylate.; [0099] A mixture of <strong>[6299-85-0]methyl 2,4-dichloropyrimidine-6-carboxylate</strong> 0.566 g (2.0 mmol) and 4-methoxy-N-methylaniline 0.274 g (2.0 mmol) with cone. HCl aq 0.5 mL in zs°-propanol 15 mL was stirred for 16 h at 23 0C. Dichloromethane 3OmL was added to the reaction mixture, and the organic layer was neutralized with sat. Na2CO3 aqueous solution, water and dried over anhydrous MgSO4. After removal of solvent, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0% to 50%) to give the titled compound in 70% yield. 1H NMR (CDCl3, 400 MHz): delta 7.14 (d, 2H, J = 9.0 Hz), 7.00 (d, 2H, J = 9.0 Hz), 6.84 (s, IH), 3.90 (s, 3H), 3.87 (s, 3H), 3.49 (s, 3H). m/e: 308.1 156 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | EXAMPLE 10; 4-Methoxyphenyl)-methyl-(2-methyl-6-phenyl-pyrimidin-4-yl) amine.; [00107] A mixture of ethyl benzylacetate 1.92g (10.0 mmol) and acetamidine hydrochloride 5.Og (53.0 mmol) with a ethanol solution (23percent wt) of EtONa 2OmL (67.5 mmol) was stirred for 36h under reflux. After removal of ethanol, the crude product was extracted with EtOAc, washed with water, and dried on anhydrous MgSO4. After removal of solvents, the intermediate 2-methyl-6- phenylpyrimidin-4-ol was dried under reduced pressure, and used without further purification. A mixture of 2-methyl-6-phenylpyrimidin-4-ol 0.93 g (5.0 mmol) and POCI3 5 mL was heated under reflux for 3 h. After cooling, excess of POCI3 was removed under reduced pressure, and the crude product was diluted with CHCI3. The solution was poured into ice-water, washed with water, and dried on anhydrous MgSO4. Removal of CHCI3 gave <strong>[2915-15-3]4-chloro-2-methyl-6-phenylpyrimidine</strong> (EMI-mass: 206 [M]+) in 90percent yield (98percent purity). A solution of 4-chloro-2-methyl-6- phenylpyrimidine 0.206 g (1.0 mmol) and 4-methoxy-N-methylaniline 0.137 g (1.0 mmol) with cone. HCl 0.2 mL in zsoe-propanol 5 mL was stirred at 23 0C for 16 h. The solution was concentrated under reduced pressure, diluted with CH2Cl2 30 mL, washed with sat. nua2Cpsi3 aqueous solution, and dried on anhydrous MgSO4. After removal of solvents, the crude product was purified with gradient column chromatography (EtOAc/hexanes, 0percent to 60percent) to give titled product in 80percent yield. 1H NMR (CD3OD, 400 MHz): delta 7.80-7.76 (m, 2H), 7.39-7.36 (m, 3H), 7.22 (d, 2H, J = 9.0 Hz), 6.99 (d, 2H, J = 9.0 Hz), 6.40 (s, IH), 3.86 (s, 3H), 3.51 (s, 3H), 2.66 (s, 3H). m/e: 306.2506 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); sodium t-butanolate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h; Inert atmosphere; | |
92% | With sodium t-butanolate In tetrahydrofuran; <i>tert</i>-butyl alcohol at 20℃; for 2h; Inert atmosphere; | 24 EXAMPLE TWENTY-THREE: General Experimental Procedures for Examples Described in Figure 11, Table 7; General Procedure BAn oven-dried test tube, which was equipped with a magnetic stir bar and fitted with a teflon septum, was charged with the precatalyst (0.01 equiv.) and NaOt-Bu (120 mg, 1.2 mmol). The vessel was evacuated and backfilled with argon (this process was repeated a total of 3 times) and then the aryl chloride (1.0 mmol), 2M methylamine solution in THF (1 mL, 2.0 mmol), and t-BuOH (ImL) were added in succession via syringe (aryl chlorides that were solids at room temperature were added with the precatalyst and base). The solution was allowed to stir at room temperature until starting aryl chloride was completely consumed as monitored by GC. The reaction mixture was then diluted with ethyl acetate, washed with aqueous NH4Cl, dried over Na2S(M concentrated in vacuo, and purified via column chromatography on silica gel.Procedure C; General procedure A was used with the following modification: 2 M methylamine solution in THF (1 mL, 2.0 mmol), and t-BuOH (4 mL) were premixed and added to the reaction vessel.; EXAMPLE TWENTY-FOUR: Synthesis of 4-Methoxy-7V-methylaniline (Figure 11, Table 7, entry 1); Following general procedure A, a mixture of 4-chloroanisole (123 μL, 1.0 mmol),2M methylamine (1 mL, 2.0 mmol), NaOt-Bu (120 mg, 1.2 mmol), BrettPhos precatalyst 10 (8 mg, 0.01 mmol), and t-BuOH (1 mL) was stirred at room temperature for 2 h. The crude product was purified via column chromatography (20:1 CH2Cl2ZMeOH) to provide the title compound as a yellow liquid that turned into a tan solid upon standing (126 mg, 92%). 1H NMR (400 MHz, CDCl3) δ: 6.80 (dt, J= 9.0, 2.3 Hz, 2H), 6.59 (dt, J= 9.0, 2.3 Hz, 2H), 3.76 (s, 3H), 3.46 (bs, IH), 2.81 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.2, 143.9, 115.1, 113.8, 56.1, 31.8 ppm. AIi, H. L; Tomita, K.; Akaho, E.; Kambara, H.; Miura, S.; Hayakawa, H.; Ashida, N.; Kawashima, Y.; Yamagishi, T.; Ikeya, H.; Yoneda, F.; Nagamatsu, T. Bioorg. Med. Chem. 2007, 15, 242. |
79% | With Pd2(dba)4; potassium <i>tert</i>-butylate; C40H66P2 In tetrahydrofuran at 20℃; for 1.5h; Inert atmosphere; Schlenk technique; Glovebox; |
With sodium t-butanolate In toluene at 85℃; for 30h; Inert atmosphere; Sealed vial; | ||
With copper In water at 100℃; for 36h; | ||
With 5-(di-tert-butylphosphino)-1′, 3′, 5′-triphenyl-1′H-[1,4′]bipyrazole; bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; sodium t-butanolate In toluene at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In water; isopropyl alcohol at 20℃; | |
76% | In isopropyl alcohol at 20℃; for 12h; | 6.6. General method for the synthesis of compounds 1-10 General procedure: To a 100 mL round-bottomed flask substituted-4-chloroquinazolines(1 equivalent), appropriate anilines (1.2 equivalents) and isopropanol(10 mL) were added and stirred at room temperature for 12 h. Thecompounds precipitated as HCl salts, which were filtered and dried invacuo over P2O5 to afford the desired compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With hydrogenchloride; In isopropyl alcohol; at 110℃; for 6h;Microwave irradiation; | N-(4-methoxyphenyl)-N,2-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (AAG20); Compound 4 (0.005 mol, 0.835 g) was added to a solution of 4-methoxy-N-methylaniline (5, 0.006 mol, 0.822 g) in i-propanol (10 ml) with drops of conc. HCl. The resulting solution was transferred to a microwave vial (20 ml) and irradiated at 110 C. After 6 h, the reaction was completed and AAG20 was obtained after the chromatographic purification as a white solid (1.01 g) with 80% yield. TLC Rf=0.85 (CH3OH:CHCl3=1:5). 1H NMR (DMSO-d6): delta 2.65 (s, 3H, 2-CH3), 3.62 (s, 3H, N-CH3), 3.84 (s, 3H, OCH3), 6.99 (bs, 4H, C6H4), 7.11-7.13 (d, 1H, 5-H), 7.39-7.41 (d, 1H, 6-H), 12.44 (s, 1H, 7-H, D2O exchanged). Anal. Calcd. (C15H16N4O. 0.3688 CHCl3.), C, 59.10; H, 5.28; N, 17.94; Found C, 58.98; H, 5.65; N, 18.16. |
80% | With hydrogenchloride; In water; isopropyl alcohol; at 120℃; for 4h;Microwave irradiation; | The synthesis of target compound 3 (Scheme 1C), started with the synthesis of a reported method for compound i.?3 2-Bromo-i,i-diethoxyethane (compound 10) was reacted with ethyl2-cyanoacetate to obtain compound 1 lwhich was cyclized to compound 12 using acetamidine hydrochloride under basic conditions. Chlorination of compound 12 using POC13 provided compound 13 in 80% yield. Displacement of the chloride of compound 13 with 4-methoxy-N- methyl aniline (compound 14) and catalytic amounts of HC1 in isopropanol, provided compound1. Methylation of compound 1 with Mel under basic conditions afforded compound 3 in 85% yield. The synthesis of target compound 5 (Scheme 1C), involved N-formylation of 4-methoxy- 2-methylanline (compound 15) to afford compound 16 in 70% yield. LAH reduction of compound 16 provided substituted aniline compound 17. Displacement of the chloride of compound 13 with anilines (compounds 15 and 17) and catalytic amounts of HC1 in isopropanol provided compounds 4 and 5 (75% and 70% respectively). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium acetate; In tetrahydrofuran; water; at 60 - 70℃; for 3h; | A mixture of <strong>[105763-77-7]2,4-dichloro-6-methoxy-quinazoline</strong> (0.5 g, 2.18 mmol), (4-methoxy-phenyl)-methyl-amine (0.35 g, 2.61 mmol) and sodium acetate (0.21 g, 2.61 mmol) in 8 mL of solvent (1:1 THF:water) was stirred at 60-70 C. for 3 h. The reaction mixture was concentrated and the resulting solid was dissolved in ethyl acetate and filtered through a pad of silica, washing with 40% ethyl acetate/hexane. The filtrate was concentrated under reduced pressure to give 0.7 g of the title compound (98% yield). 1H NMR (DMSO-d6) delta 7.6 (d, 1H), 7.36-7.31 (m, 3H), 7.08-7.05 (dd, 2H), 6.2 (d, 1H), 3.79 (s, 3H), 3.5 (s, 3H), 3.28 (s, 3H); LC-MS (ESI+; 330 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With RuPhos palladacycle; lithium hexamethyldisilazane; ruphos In toluene at 80℃; for 16h; Inert atmosphere; Sealed vial; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.030 g (11%) | Example 93 N-((1H-Benzo[d]imidazol-5-yl)methyl)(4-methoxyphenyl)-N-methylmethanamine The compound was synthesized starting from benzimidazol-5-carbaldehyde (146 mg; 1 mmol; 1 eq.), 4-methoxy-N-methylaniline (137 mg g; 1 mmol; 1 eq.); NaBH(AcO)3 (318 mg; 1.5 mmol; 1.5 eq.) and AcOH (0.095 ml; 1.5 mmol; 1.5 eq.) as described above. Yield: 0.030 g (11%); MS m/z: 268.3 [M+H]+; 1H-NMR (400 MHz, DMSO d6): delta 2.89 (s, 3H); 3.64 (s, 3H); 4.53 (s, 2H); 6.71-6.78 (m, 4H); 7.05-7.07 (m, 1H); 7.35 (br s, 1H); 7.49 (d, 1H, 3J=8.3 Hz); 8.13 (s, 1H); 12.35 (br s, 1H); HPLC (METHOD [A]): rt 6.28 min (90.3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With quinazoline In tetrahydrofuran; water at 100℃; for 0.166667h; Microwave irradiation; | 1.3. Synthesis of 6-halo-2-phenyl-substituted 4-anilinoquinazolines General procedure: In a microwave vial, the given aniline (1.05 equiv), 4-chloro-6-halo-2-phenylquinazoline (1.0 equiv), and a mixture of THF/H2O 1:1 (6 mL.mmol-1 ofquinazoline) were added. The reaction mixture was stirred further for theindicated times at 100 °C in a microwave reactor after which the reaction wasquenched with saturated aqueous NaHCO3 solution. The aqueous phase wasextracted with AcOEt (3 ×), the organic layers were dried with MgSO4, andconcentrated under reduced pressure. After that, flash column chromatographyusing suited hexanes/ethyl acetate mixtures afforded the isolated products. |
75% | With hydrogenchloride In isopropyl alcohol | |
58% | In isopropyl alcohol at 20℃; for 12h; | 6.6. General method for the synthesis of compounds 1-10 General procedure: To a 100 mL round-bottomed flask substituted-4-chloroquinazolines(1 equivalent), appropriate anilines (1.2 equivalents) and isopropanol(10 mL) were added and stirred at room temperature for 12 h. Thecompounds precipitated as HCl salts, which were filtered and dried invacuo over P2O5 to afford the desired compounds. 6.6.1. N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine (1) Using the general method described above, 12a (0.150 g, 0.840mmol) and 4-methoxy-N-methylaniline (14) (0.138 g, 1.01 mmol) werereacted for 12 h. At the end of the reaction, solvent was evaporated,silica gel and methanol were added, and the methanol evaporated invacuo to give a dried plug. The reaction mixture was purified by flashchromatography using chloroform/methanol to afford 1 as a brownsolid (0.136 g, 58%). TLC Rf = 0.8 (MeOH:CHCl3; 1:5); mp,99.1-101.2 C; 1H NMR, DMSO-d6 (400 MHz): 2.66 (s, 3H, 2-CH3), 3.60(s, 3H, NCH3), 3.81 (s, 3H, OCH3), 6.88-6.90 (d, 1H, J = 8.35, Ar),7.04-7.06 (d, 2H, J = 8.89, Ar), 7.14-7.18 (t, 1H, J1 = 7.49, J2 = 7.49,Ar), 7.30-7.32 (d, 2H, J = 8.78, Ar), 7.68-7.75 (m, 2H, Ar). Anal. Calcd.for C17H17N3O 0.52HCl: C, 68.46; H, 5.92; N, 14.08. Found C, 68.50; H,6.24; N, 13.80; Cl, 4.54. |
In dichloromethane; isopropyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.6% | (Example 2)Synthesis of IrHCl2 ( ( R)-binap ) ( -Me-p-ani s idine )Into a nitrogen-purged Schlenk tube, [ IrCl ( coe ) 2 ] 2 (200 mg, 0.45 mmol), (R)-BINAP (308 mg, 0.49 mmol), and toluene (10 ml) were added. After stirring at room temperature for one hour, N-methyl-p-anisidine (102 mg, 0.74 mmol) was added, followed by stirring at the same temperature for 30 minutes. Then, concentrated hydrochloric acid (160 μ, 2.10 ramol) was added. After stirring for 4 hours, the precipitates were filtrated to obtain the light yellow complex (270 mg , yield: 59.6%) .ΧΗ NMR (C6D6) : δ 8.70-6.20 (m, 36H), 3.12 (s, 3H), 2.82 (s, 3H) , -20.26 (dd, J = 14.1, 19.5 Hz, 1H);31P NMR (C6D6) : δ-0.18 (m) , -3.57 (m) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: N-methyl-N-(4-methoxyphenyl)amine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: 1-bromo-2-(bromomethyl)-4,5-dimethoxybenzene In N,N-dimethyl-formamide at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | at 140℃; for 0.333333h;Microwave irradiation; | General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | at 160℃; for 0.5h;Microwave irradiation; | General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | at 160℃; for 0.25h;Microwave irradiation; | General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | at 160℃; for 0.5h;Microwave irradiation; | General procedure: Method B (microwave irradiation): A mixture of 2 (1.0 mmol), substituted aniline (1.5 mmol), and anhydrous potassium carbonate (414 mg, 3.0 mmol) in 3 mL of t-BuOH was heated at 120-160 C with microwave-assistance for 10-30 min with stirring. The reaction mixture was then poured into ice-water, pH adjusted to ?3.0 with aq HCl (2 N), and solid crude product was filtered. The product was then purified by the same methods as in Method A above. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane; 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 90℃; for 1h; Inert atmosphere; Schlenk technique; chemoselective reaction; | |
99% | With phenylsilane; triphenylphosphine In tetrahydrofuran at 120℃; for 24h; Autoclave; Green chemistry; | |
95% | With cyclopentadienyl iron(II) dicarbonyl dimer; phenylsilane; triphenylphosphine In acetonitrile at 100℃; for 36h; Schlenk technique; Sealed tube; |
92% | With methanesulfonic acid; hydrogen; ruthenium(III) acetylacetonate; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In tetrahydrofuran at 140℃; for 24h; Autoclave; Inert atmosphere; | |
92% | With 1,10-Phenanthroline; diphenylsilane; Zinc acetate In acetonitrile at 120℃; for 24h; Autoclave; | |
91.2% | With carboxymethyl-dodecyl-dimethyl-ammonium betaine; polymethylhydrosiloxane In acetonitrile at 70℃; for 12h; Schlenk technique; | 5 Take a strictly dry Shrek reaction tube (Schlenk tube), connect a balloon filled with carbon dioxide to the Schlenk tube through the side tube, and clean it 3 times, Sequentially add dodecyl dimethyl amine caprolactone (5mol% relative to amine),4-Methoxy-N-methylaniline (0.25mmol), polymethylpolysiloxane PMHS (1mmol) and CH3CN (2mL), Schlenk tube heated at 70°C for 12h, Cool to room temperature, release the CO2 in the balloon, add EtOAc (10 mL) to the mixture to quench the reductive reaction, and extract three times with CH2Cl2. The concentrated organic layer was dried over anhydrous Na2SO4 and evaporated under vacuum, purify by silica gel column chromatography with petroleum ether/ethyl acetate to obtain the corresponding product. |
90% | With phenylsilane In tetrahydrofuran at 120℃; for 24h; | |
90% | With sodium tetrahydridoborate In 1,4-dioxane at 100℃; for 24h; Autoclave; | |
90% | With diphenylsilane; C21H41N3NiP2 In acetonitrile at 120℃; for 24h; Autoclave; | |
90% | With stannous trifluoromethanesulfonate; hydrogen; Co(OAc)2.4H2O; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In ethanol at 125℃; for 24h; Glovebox; Green chemistry; | |
87% | With diphenylsilane; caesium formate In acetonitrile at 50℃; for 6h; Green chemistry; | |
87% | With dimanganese decacarbonyl; phenylsilane; C29H33N2P In acetonitrile at 100℃; for 15h; | |
86% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 100℃; for 48h; Schlenk technique; | |
80% | With tris(pentafluorophenyl)borate; phenylsilane In acetonitrile at 140℃; for 24h; Autoclave; | |
78% | With sodium tetrahydridoborate In 1,4-dioxane at 100℃; for 24h; Autoclave; Green chemistry; | |
74% | With C40H46N2; 9-bora-bicyclo[3.3.1]nonane In tetrahydrofuran at 40℃; for 24h; | |
66% | With 2-Amino-6-methylpyridine; trimethylamine-borane In 1,2-dichloro-ethane at 100℃; for 12h; Schlenk technique; chemoselective reaction; | |
65% | With triphenylborane; phenylsilane In neat (no solvent) at 30℃; for 8h; Glovebox; Schlenk technique; | |
47% | With C37H46N4; 9-bora-bicyclo[3.3.1]nonane In toluene at 100℃; for 1.5h; Glovebox; Inert atmosphere; Schlenk technique; | |
45% | With phenylsilane In N,N-dimethyl-formamide at 90℃; for 24h; Schlenk technique; | |
With C27H36Cl2N2Zn; phenylsilane In tetrahydrofuran at 100℃; for 20h; | ||
35 %Chromat. | With Ru(1,1,1-tris(diphenylphosphinomethyl)ethane)(trimethylene methane); hydrogen; bis(trifluoromethanesulfonyl)amide In tetrahydrofuran at 150℃; for 10h; Autoclave; Inert atmosphere; | |
90 %Chromat. | With hydrogen In neat (no solvent) at 200℃; for 24h; | |
87 %Spectr. | With N,N,N-tributylbutan-1-aminium fluoride; HSiPh3 In tetrahydrofuran at 50℃; for 12h; Schlenk technique; chemoselective reaction; | |
85 %Spectr. | With diphenylsilane; trimethylammonioacetate In acetonitrile at 70℃; for 12h; Inert atmosphere; | |
78 %Chromat. | With 5 wt% Re/TiO2; hydrogen In octane at 200℃; for 24h; Autoclave; chemoselective reaction; | |
92 %Spectr. | With potassium monotungstate; phenylsilane In acetonitrile at 70℃; for 12h; Schlenk technique; | |
93 %Spectr. | With copper carbonate hydroxide; phenylsilane; 1,4-di(diphenylphosphino)-butane In acetonitrile at 60℃; for 12h; Schlenk technique; | |
99 %Chromat. | With phenylsilane; acetylcholine acetate In acetonitrile at 50℃; for 6h; Green chemistry; | |
82 %Spectr. | Stage #1: carbon dioxide; N-methyl-N-(4-methoxyphenyl)amine With C122H75N12O9Zn5(1+)*HO(1-) In neat (no solvent) at 100℃; for 0.166667h; Stage #2: With phenylsilane In neat (no solvent) at 100℃; for 24h; chemoselective reaction; | |
With phenylsilane In N,N-dimethyl-formamide at 75℃; for 20h; Green chemistry; | ||
With hydrogen In octane at 120℃; for 24h; High pressure; | ||
95 %Chromat. | With polytetrafluoroethylene; hydrosilane at 100℃; for 24h; | 11 Example 11 Weigh 0.456 g of the bromo-n-hexyl ethyl tetramethyl guanidine ionic liquid prepared above as a catalyst and 0.157 g (1 mmol) of 4-methoxy-N-methylaniline on a stainless steel lined with polytetrafluoroethylene In the reactor, the temperature is raised to 100°C, and then carbon dioxide with a pressure of 1 MPa is introduced to react for 24 hours. The reaction equation is as follows: After the reaction is over, cool to room temperature naturally, add the internal standard biphenyl and stir to dissolve it completely, then add 0.5mL of the reaction solution to 2mL of acetonitrile solvent to dilute, use gas chromatography to determine the reaction yield, the measured yield is 95% . Then, ethyl acetate and water are added to the reaction solution for extraction to disperse the ionic liquid and the product, and the aqueous phase is spin-dried to obtain the ionic liquid. After the recovered ionic liquid catalyst is vacuum dried for 2 hours, it can be recycled as a catalyst again. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 20℃; | |
94% | With triethylamine In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | |
89% | With potassium carbonate In water monomer; acetone at 0℃; Inert atmosphere; Sealed tube; Schlenk technique; | 2.1 General Procedure for the phenylmethacrylamide derivatives General procedure: Acyloyl chloride (2.0 eq.) was added to a stirred solution of potassium carborate (2.0 eq.) in distilled water (5.0 ml) and acetone (20 ml) at 0°C under nitrogen atmosphere. Then anline (1.0 eq.) was added dropwise into the mixture. The suspension was stirred at 0°C. after filtration, the mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic filtrate was evaporated under vacuum to dryness and the residue was purified by column chromatography to yield the desired product. |
62% | With potassium carbonate In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; | N-(4-Methoxyphenyl)-N-methylmethacrylamide (2d) A solution of 1.16 g (8.5 mmol) of 4-methoxy-N-methylaniline and 0.82 mL (8.5mmol) of methacryloyl chloride in 85 mL of dry THF was stirred under Argon at 0 degrees and treated with 1.37g (9.9 mmol) of potassium carbonate. The reaction mixture was stirred for 2 h, followed by addition of 2M HCl and extraction with ethylacetate. The aqueous layer was further extracted by ethyl acetate (2 x 50 mL) and the combined organic phases were dried over Na2SO4. The solvent was removed byrotary evaporation and the crude product was purified by column chromatography. Yield :1.08 g, 62%; White solid, 1H NMR (500 MHz, DMSO): δ 7.19-7.14 (m, 2H),6.94-6.88 (m, 2H), 4.97 (s, 1H), 4.82 (s, 1H), 3.74 (s, 3H), 3.18 (s, 3H), 1.59 (s, 3H); 13C NMR (125 MHz, DMSO): δ 170.69, 157.77, 140.69, 137.25, 127.86, 117.89,114.26, 55.24, 37.24, 20.17; HRMS-(ESIpos) (m/z): M+ calcd for C12H15N1O2Na,228.099497; found 228.099590. |
With potassium carbonate In toluene at 80℃; for 12h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 2h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 6h; | ||
With triethylamine In dichloromethane at 20℃; | ||
With triethylamine In dichloromethane | ||
With triethylamine In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tris(pentafluorophenyl)borate In dibutyl ether at 100℃; Schlenk technique; Inert atmosphere; | |
92% | With phenylsilane; copper diacetate In dibutyl ether at 80℃; for 8h; Schlenk technique; Green chemistry; | |
92% | With C20H25IrN2O3 at 50℃; for 20h; |
74% | With platinum on carbon; phenylsilane In toluene at 80℃; for 15h; | |
74% | With platinum on activated charcoal; phenylsilane In toluene at 80℃; for 15h; Schlenk technique; Inert atmosphere; | 9 Preparation of compound IV-3 An activated carbon supported platinum catalyst (Pt / C, 0.06 mg platinum, 0.0003 mmol, 0.1 mol%) was added to a 10 mL Schlenk tube,After evacuation of argon, add 1 mL of solvent (toluene).Under argon protection, to the above system,Separately, phenylsilane (78.9 mg, 0.75 mmol) was added successively,III-3 (R2 = p-methoxyphenyl, R3 = methyl) (41.2 mg, 0.3 mmol) and formic acid (27.6 mg, 0.6 mmol).The reaction was carried out at 80 ° C with stirring for 15 hours.After completion of the reaction, 3 mL of ethyl acetate was added to the system,The reaction was quenched with aqueous sodium hydroxide (3 mol / L, 3 mL)Ethyl acetate (3 x 10 mL), the organic phase was separated,Dried over anhydrous Na2SO4, filtered,The solvent was removed by rotary evaporation.The residue was purified by column chromatography on ethyl acetate / petroleum ether = 1: 100 mixed solvent,The product was isolated and purified to give the target product IV-333.6 mg in 74% yield. |
71% | With platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex; 1,3-bis-(diphenylphosphino)propane; phenylsilane In dibutyl ether at 20℃; for 18h; Schlenk technique; Inert atmosphere; | |
77 %Spectr. | With [bis(2-methylallyl)cycloocta-1,5-diene]ruthenium(II); bis(trifluoromethanesulfonyl)amide; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In tetrahydrofuran-d8 at 150℃; for 24h; Inert atmosphere; Schlenk technique; Glovebox; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C / Inert atmosphere; Schlenk technique 1.2: 20 °C / Inert atmosphere; Schlenk technique 2.1: trifluoroacetic acid / dichloromethane / 48 h / 40 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0.02 h / 5 °C 2: hydrogenchloride / water / 120 °C | ||
Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 0 - 25 °C 2: trifluoroacetic acid / dichloromethane / 25 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(II) ferrite In N,N-dimethyl acetamide at 140℃; for 3h; Inert atmosphere; | |
72% | With [Cu2(1,4-benzenedicarboxylate)2(1,4-diazabicyclo[2.2.2]octane)]n In N,N-dimethyl acetamide; water at 120℃; for 3h; Inert atmosphere; | 2.2. Catalytic studies General procedure: In a typical experiment, a pre-determined amount of the Cu2(BDC)2(DABCO) was added to the flask containing a mixture ofphenylacetylene (0.11 mL, 1 mmol), N-methylaniline (0.22 mL,2 mmol), tert-butyl hydroperoxide (TBHP) (70% in water, 0.41 mL,3 mmol) as an oxidant, and n-hexadecane (0.1 mL) as an internalstandard in N,N-dimethylacetamide (DMA) (4 mL) under an argonatmosphere. The catalyst percentage was calculated based on themolar ratio of copper/phenylacetylene. The reaction mixture wasstirred at 120 °C for 180 min. The reaction conversion was monitoredby withdrawing aliquots from the reaction mixture at differenttime intervals, quenching with water (1 mL), drying overanhydrous Na2SO4, analyzing by GC with reference to n-hexadecane,and further confirming product identity by GC-MS, and 1HNMR and 13C NMR. To investigate the recyclability of the Cu2(BDC)2(DABCO), the catalyst was filtered from the reaction mixtureafter the experiment, washed with copious amounts of DMA, driedat 140 °C under vacuum in 6 h, and reused if necessary. For theleaching test, a catalytic reaction was stopped after 10 min, analyzedby GC, and filtered to remove the solid catalyst. The reactionsolution was then stirred for a further 170 min. Reaction progress,if any, was monitored by GC as previously described. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With copper diacetate; triethylamine; In dichloromethane; at 0 - 5℃; for 4h;Sonication; Green chemistry; | General procedure: Naphthylboronic acid (0.25 g, 1.5 mmol) was added with 0.094 g of phenol (1.0 mmol) to 15 mL of DCM. Copper(II) acetate (0.36 g, 2.0 mmol) was then added along with triethylamine (0.5g, 5.0 mmol), and the dismembrator horn placed in the reaction vessel. The sonicator was set to 55 watts and the reaction was allowed to proceed for 4 hours (1 minute pulse with a 3 second rest). Post reaction, the product was isolated by column chromatography. Product yields were determined by weight and purity was confirmed by GC/MS and NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With C19H29N5OP(1+)*F6P(1-) In dichloromethane at 20℃; | 1 4.1.1 Tert-butyl(S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2) A solution of 62 (tert-butoxycarbonyl)-l-phenylalanine (1, 8.75mmol, 2.3g) in 15mL 63 dichloromethane was added PyBop (10.9mmol, 5.7g) at 0°C, and the mixture stirred for 0.5h. Subsequently, 64 DIEA (21.87mmol, 3.61mL) and 25 4-methoxy-N-methylaniline (7.29mmol, 1.0g) were added to the mixture and then stirred at room temperature for another 8-9h (monitored by TLC). The resulting mixture was evaporated under reduced pressure and the residue was initially washed by 1N HCl and extracted with ethyl acetate (3×20mL). Then, the combined organic layer was washed with saturated sodium bicarbonate (3×50mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford corresponding crude intermediate 65 2 as yellow oil with a yield of 94%. 1H NMR (400MHz, DMSO-d6) δ 7.21 (d, J=8.4Hz, 3H), 7.15 (d, J=7.1Hz, 2H), 7.02 (d, J=8.4Hz, 2H), 6.85-6.75 (m, 2H), 4.15 (q, J=5.4Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.81-2.54 (m, 2H), 1.30 (s, 9H). 13C NMR (100MHz, DMSO) δ 172.21, 158.98, 155.74, 138.53, 136.13, 129.28, 128.47, 126.70, 115.21, 78.33, 55.94, 53.53, 37.86, 37.10, 28.65. ESI-MS: m/z 385.4 (M+1)+, C22H28N2O4 (384.2) |
88% | Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; | 4.1.1. Tert-butyl(S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (2) A solution of (tert-butoxycarbonyl)-L-phenylalanine (1, 2.90 g,10.93 mmol, 1.5 eq.) in 20 mL dichloromethane was added PyBop(5.69 g, 10.93 mmol, 1.5 eq.) at 0 C, and the mixture stirred for0.5 h. Subsequently, DIEA (3.61 mL, 21.87 mmol, 3 eq.) and 4-methoxy-N-methylaniline (1.0 g 7.29 mmol, 1 eq.) were added tothe mixture and then stirred at room temperature for another 6 h(monitored by TLC). The resulting mixture was evaporated underreduced pressure and the residue was initially washed by 1N HCland extracted with ethyl acetate (3 20 mL). Then, the combinedorganic layer was washed with saturated sodium bicarbonate(3 20 mL), dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure to afford corresponding crudeproduct, which was purified by flash column chromatography toafford intermediate 2 as yellow oil with a yield of 88%. 1H NMR(400 MHz, DMSO-d6) d 7.22 (d, J 8.3 Hz, 2H, Ph-H), 7.20e7.11 (m,3H, Ph-H), 7.09 (d, J 8.2 Hz, 1H, NH), 7.03 (d, J 8.6 Hz, 2H, Ph-H),6.79 (d, J 7.3 Hz, 2H, Ph-H), 4.27e4.06 (m, 1H, CH), 3.81 (s, 3H,OCH3), 3.13 (s, 3H, NCH3), 2.75 (dd, J 13.4, 3.8 Hz, 1H, PhCH), 2.61(dd, J 13.3, 10.3 Hz, 1H, PhCH), 1.30 (s, 9H, C(CH3)3). 13C NMR(100 MHz, DMSO-d6) d 172.22 (C]O), 158.98, 155.75 (C]O), 138.53(2 C), 136.12 (2 C), 129.28 (2 C), 128.47 (2 C), 126.70, 115.21(2 C), 78.33, 55.94, 53.55, 37.86, 37.07, 28.65 (3 C). ESI-MS: m/z385.4 (M1), 407.5 (M23). C22H28N2O4 [384.5]. |
88% | Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; |
88% | Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine at 20℃; for 6h; | 5.1.1. General procedure for the synthesis of 2a-2c General procedure: To a solution of (tert-butoxycarbonyl)-L-phenylalanine or (tertbutoxycarbonyl)-3,5-difluoro-L-phenylalanine (1.5 eq.) in 20 mLdichloromethane was added PyBop (1.5 eq.) at 0 C, and themixture was stirred for 0.5 h. Subsequently, DIEA (3 eq.) and Nmethylanilineor 4-methoxy-N-methylaniline (1 eq.) were added tothe mixture and then stirred at room temperature for another 6 h(monitored by TLC). The resulting mixture was evaporated underreduced pressure, and the residue was initially washed by 1 N HCland extracted with ethyl acetate (3 20 mL). Then, the combinedorganic layer was washed with saturated sodium bicarbonate(3 20 mL), dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure to afford a corresponding crudeproduct, purified by flash column chromatography to afford intermediate2a-2c. |
79% | Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 8h; | 4.1.1. Synthesis of tert-butyl (S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate (6) A solution of (tert-butoxycarbonyl)-L-phenylalanine (2.65 g, 10.00mmol) in 15 mL dichloromethane was added PyBop (5.70 g, 15.00mmol) at 0, and the mixture stirred for 0.5 h. Subsequently, DIEA(3.30 mL, 20.00 mmol) and 4-methoxy-N-methylaniline (1.37 g, 10.00mmol) were added and then the mixture was stirred at room temperaturefor another 8 h (monitored by TLC), evaporated under reducedpressure and the residue was initially washed by saturated sodium bicarbonate(50 mL) and extracted with ethyl acetate (3 × 10 mL). Thenthe combined organic layer was washed by 1 N HCl and extracted withethyl acetate (3 × 10 mL), dried over anhydrous Na2SO4, filtered, andconcentrated under reduced pressure to afford corresponding crude intermediate6 as yellow oil with a yield of 79%. 1H NMR (400 MHz,DMSO-d6) δ 7.21 (d, J = 8.4 Hz, 3H, Ph-H + NH), 7.15 (d, J = 7.1 Hz,2H, Ph-H), 7.02 (d, J = 8.4 Hz, 2H, Ph-H), 6.85-6.75 (m, 2H, Ph-H), 4.15(q, J = 5.4 Hz, 1H, CH), 3.80 (s, 3H, OCH3), 3.12 (s, 3H, NCH3),2.81-2.54 (m, 2H, CH2), 1.30 (s, 9H, CH3 × 3); 13C NMR (100 MHz,DMSO-d6) δ 172.2, 158.9, 155.7, 138.5, 136.1, 129.2, 128.4, 126.7,115.2, 78.3, 55.9, 53.5, 37.8, 37.1, 28.6. ESI-MS: m/z 385 [M + H]+,C22H28N2O4 (384.2). |
1.34 g | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; | JB.1 Intermediate JB- 1 (S)-tert-butyl (1-((4-methoxyphenyl) (methyl)amino)-1-oxo-3-phenylpropan-2- yl)carbamate HATU (1.5 g, 4.0 mmol) was added to a stirred solution of 4-methoxy-N- methylaniline (500 mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.0 mmol) in DMF (20 mL) and DIPEA (1.3 mL, 7.3 mmol) and the reaction mixture was stirred at RT for 4h. The reaction was concentrated and the residual crude oil was partitioned between EtOAc (60 mL) and 1/2 sat. NaHCO3 (aq) (60 mL). The organic component was washed with brine (40 mL), dried (Mg504), filtered, concentrated and purified using a Biotage Horizon (80g5i02, 10-40% EtOAc/hexanes) to yield (5)-tert-butyl (1-((4- methoxyphenyl)(methyl)amino)- 1 -oxo-3 -phenylpropan-2-yl)carbamate (1.34 g) as a clear amber viscous oil. LC-MS retention time = 3.17 mm; mlz = 385.3 [M+H]. (Column: Phenonenex-Luna C18 2.0 x 50mm 3 pm. Solvent A = 95% Water:5% Acetonitrile:10 miVi NH4OAc. Solvent B = 5% Water:95% Acetonitrile:10 miViNH4QAc. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time= 4 mm. Wavelength = 220). ‘H NMR (400MHz, CDC13) ö 7.25 - 7.20 (m, 3H),7.03 - 6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (q, J=7.4 Hz, 1H), 3.83 (s, 3H),3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s,9H). |
1.34 g | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 4h; | HATU (1.52 g, 4.01 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline (500 mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.01 mmol) iln DMF (20 mL) and DIPEA (1.27 mL, 7.29 mmol) and the reaction mixture was stirred at rt for 4 h. The reaction mixture was concentrated and the crude oil was then partitioned between EtOAc (-60 mL) and 1/2 sat. NaHCCb (aq.) (-60 mL). The organic component was washed with brine (-40 mL), dried (MgS04), filtered and concentrated. The residual oil was then purified using a Biotage Horizon (80g SiC , 10- 40% EtOAc/hexanes) to yield Intermediate 1 (1.34 g) as clear amber viscous oil. LC-MS retention time = 3.17 min; m/z = 285.3 [M+H-Boc]+. (Column: Phenomenex Luna C18 2.0 X 50 mm 3 μιη. Solvent A = 95% Water : 5% Acetonitrile : 10 mM NH4OAc. Solvent B = 5% Water : 95% Acetonitrile : 10 mM NH4OAc. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 4 minutes, then a 1 -minute hold at 100% B. Wavelength = 220 nm). NMR (400 MHZ, CDCb) δ ppm 7.25 - 7.20 (m, 3H), 7.03 - 6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (app q, J=7.4 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H). |
1.34 g | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 4h; | JB-1 HATU (1.5 g, 4.0 mmol) was added to a stirred solution of 4-methoxy-N-methylaniline mg, 3.64 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid (1.06 g, 4.0 mmol) in DMF (20 mL) and DIPEA (1.3 mL, 7.3 mmol) and the reaction mixture was stirred at rt for 4h. The reaction was concentrated and the residual crude oil was partitioned between EtOAc (-60 mL) and 1/2 sat. NaHCC (aq) (-60 mL). The organic component was washed with brine (-40 mL), dried (MgS04), filtered, concentrated and purified using a Biotage Horizon (80 g SiC , 10-40% EtOAc/hexanes) to yield Intermediate JB-1 (1.34 g) as a clear amber viscous oil. LC-MS retention time = 3.17 min; m/z = 385.3 [M+H]+. (Column: Phenonenex-Luna C18 2.0 x 50mm 3 μιη. Solvent A = 95% Water:5% Acetonitrile: 10 mM NH4OAc. Solvent B = 5% Water:95% Acetonitrile: 10 mM NH4OAc. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 4 min. Wavelength = 220). NMR (400 MHz, CDCh) δ 7.25 - 7.20 (m, 3H), 7.03 - 6.64 (m, 6H), 5.20 (d, J=8.8 Hz, 1H), 4.53 (app q, J=7.4 Hz, 1H), 3.83 (s, 3H), 3.18 (s, 3H), 2.89 (dd, J=13.1, 7.5 Hz, 1H), 2.71 (dd, J=13.1, 6.5 Hz, 1H), 1.39 (s, 9H). |
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane for 0.5h; Cooling with ice; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; | 1 Example 1: Key Intermediate (S)-N-(1-(4-methoxyphenyl)(methyl)amino)-1-carbonyl-3-phenyl-2-yl)propynamide (4 Preparation of The starting material Boc-L-phenylalanine (1) (8.75 mmol, 2.3 g) was added to 15 mL of anhydrous dichloromethane solution. To this solution was then added 1H-benzotriazol-1-yloxytripyrrolidinylhexafluorophosphate (10.9 mmol, 5.7 g). After stirring for 0.5 h under ice bath, N,N-diisopropylethylamine (21.87 mmol, 3.61 mL) and N-methyl-4-aminoanisole (7.29 mmol, 1.0 g) were added to remove the ice bath. Stir at room temperature for 12 h. After the reaction is completed, the solvent is distilled off under reduced pressure, then saturated sodium bicarbonate solution is added to the bottle residue, and ethyl acetate is extracted; the organic layer is separated, 1N HCl solution is added, and ethyl acetate is extracted; the organic layers are combined and saturated. The brine was washed and the organic phase was dried over anhydrous sodium sulfate; Filtration and evaporation of the solvent under reduced pressure gave the intermediate compound tert-butyl-(S)-(1-((4-methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropyl- 2-Carboxylic acid (2) Crude 2.63 g, yellow oil, 94% yield, | |
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane for 0.5h; Cooling with ice; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With diisopropylamine In dichloromethane at 20℃; for 6h; | 1 Example 1: (S)-(1-((4-Methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester (2) Preparation Starting material Boc-L-phenylalanine (1) (2.90 g, 10.93 mmol, 1.5 eq.),1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (5.69 g, 10.93 mmol, 1.5 eq.) was added to 20 mL of dichloromethane and stirred for 30 min under ice bath;Then N,N-diisopropylethylamine (3.61 mL, 21.87 mmol, 3 eq.) was added.And N-methyl-4-aminoanisole (1.0 g 7.29 mmol, 1 eq.),Remove the ice bath and transfer to room temperature for stirring. TLC monitoring; after 6 hours, the reaction is completed.The solvent was distilled off under reduced pressure, and then 40 mL of saturated sodium hydrogen carbonate solution and 40 mL of dichloromethane were added to the residue, and the organic phase was separated and washed with 40 mL of 1N HCl solution.The organic phase was separated and washed with 40 mL of a saturated sodium chloride solution.The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated.The obtained crude product was separated by silica gel column chromatography (eluent EA: PE = 1:8 v/v)Getting an intermediate(S)-(1-((4-Methoxyphenyl)(methyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamic acid tert-butyl ester (2) crude product 2.48 g, yellow oil, yield 88%. | |
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dichloromethane at 0℃; for 0.5h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; | ||
Stage #1: <i>N</i>-<i>tert</i>-butoxycarbonyl-<i>L</i>-phenylalanine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: N-methyl-N-(4-methoxyphenyl)amine In N,N-dimethyl-formamide at 20℃; | Synthesis of 59: General procedure: To a solution of commercially available (tert-butoxycarbonyl)-Lphenylalanine(1.0 g, 3.8 mmol, 1 equiv.) in DMF (5 mL), HATU or T3P (2 equiv.) andDIPEA (2 equiv.) were added and the mixture was stirred at room temperature for 20min before amine (1.5 equiv.) was added. The mixture was further stirred at roomtemperature overnight. Upon completion, H2O was added and the reaction mixture wasextracted with EtOAc (3x50 mL). The organic phases were combined and washed withbrine, dried over anhydrous MgSO4, filtered and concentrated. The product waspurified by Combi-flash on silica gel using EtOAc/hexane (1:4 to 2:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.9 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | HATU (2.00 g, 5.26 mmol) was added to a stirred solution of 4-methoxy-N- methylaniline (0.601 g, 4.38 mmol), (S)-3 -(3 -bromophenyl)-2-((tert- butoxycarbonyl)amino)propanoic acid (1.508 g, 4.38 mmol) and DIPEA (2.3 mL, 13mmol) in DMF (15 mL) and the reaction mixture was stirred at RT overnight. The reaction was diluted with water (50 mL), extracted by EtOAc (2 X 40 mL) and the combined organic component was concentrated to dryness to yield the title compound (1.9 g) which was used without further purification. LC-MS retention time = 2.40 mm; mlz = 363.1 [M+H-Boc]. (Column: Phenonenex-Luna C18 2.0 x30mm 3 pm. Solvent A = 95% Water:5% Acetonitrile: 10 pM ammonium acetate. Solvent B = 5% Water:95% Acetonitrile: 10 pM ammonium acetate. Flow Rate =1.0 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 3 mm. Wavelength =220). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.58 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | HATU (0.800 g, 2.10 mmol) was added to a stirred solution of 4-methoxy-N- methylaniline (0.240 g, 1.75 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3 -(3- hydroxyphenyl)propanoic acid (0.493 g, 1.75 mmol) and DIPEA (0.92 mL, 5.3 mmol) in DMF (5 mL) and the reaction mixture was stirred at RT overnight. The reaction was diluted with water (50 mL), extracted with EtOAc (2 X 40 mL) and thecombined organic component was concentrated to dryness and purified (40g 5i02, 0-30% EtOAc/DCM) to yield the title compound (0.58 g). LC-MS retention time =1.99 mm; mlz = 399.3 [M-Hf. (Column: Phenonenex-Luna C18 2.0 x 30mm 3 pm.Solvent A = 95% Water:5% Acetonitrile: 10 pM ammonium acetate. Solvent B =5% Water:95% Acetonitrile: 10 pM ammonium acetate. Flow Rate = 1.0 mL/min.Start % B = 0. Final % B = 100. Gradient Time = 3 mm. Wavelength = 220). ?HNMR (400MHz, CHLOROFORM-d) oe 7.10 (t, J=7.8 Hz, 1H), 6.91 - 6.66 (m, 5H),6.52 (d, J=7.6 Hz, 1H), 6.46 (s, 1H), 5.57 (br. s., 1H), 5.20 (d, J=7.6 Hz, 1H), 4.52 (d,J=7.8 Hz, 1H), 3.81 (s, 3H), 3.19 (s, 3H), 2.84 (dd, J=13.0, 7.8 Hz, 1H), 2.68 (dd,J=12.8, 6.2 Hz, 1H), 1.40 (br. s., 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In hexane at 70℃; Dean-Stark; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: N-methyl-N-(4-methoxyphenyl)amine With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: sym-dibenzo-1,5-cyclooctadiene-3,7-diyne In tetrahydrofuran; hexane at -78 - 25℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: carbon disulfide; N-methyl-N-(4-methoxyphenyl)amine With potassium hydroxide In dimethyl sulfoxide at 20℃; for 2h; Schlenk technique; Green chemistry; Stage #2: Pentafluorobenzonitrile In dimethyl sulfoxide at 20℃; for 2h; Schlenk technique; Green chemistry; regioselective reaction; | General procedure for the synthesis of 2,3,5,6-tetrafluorobenzonitrile-containing Dithiocarbamic Acid Esters (the synthesis of 4a as example) General procedure: Compound 1a (0.2 mmol, 39.5 mg), carbon disulfide 2 (0.4mmol, 30.4 mg), and K3PO4 (0.3 mmol, 63.5 mg) were weighted to a dried 10 mL schlenk flask under air. Then DMSO (2.0 mL) was added. The mixture was stirred at room temperature for approximately two hours. After substrate 1a completely disappeared (monitored by TLC), pentafluorobenzonitrile 3a (0.26 mmol, 50.4 mg) was added and the mixture continued stirring for another two hours. After the completion of the reaction (by TLC), water (5.0 mL) was added to the reaction media and extracted with CH2Cl2 (3×10.0 mL). The combined organic layers were washed with brine, and dried over anhydrous MgSO4. After removal of the solvent, the residue was purified by flash column chromatography on silica gel to give the desired product 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[205445-52-9](S)-2-((tert-butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid</strong> (0.5 g, 1.66 mmol), diisopropyleihyiamine (0.58 mL, 6,0 mmol) and HATU (0.76 g, 2.0 mmol) in DMF (5 mL), 4~meihoxy~M-methylariiiine (0.3 g, 2.22 mmol) was added to the solution after 10 minutes. The reaction was stirred at room temperature for overnight. The mixture was diluted with EiOAc (50 mL) and washed with brine. The organic layer was dried with NasSC^ and concentrated. The crude product was purified by flash column. MS (m/z) 421.2 [M+H]+. | ||
1.39 g | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | HATU (1.39 g, 3.65 mmol) was added to a stirred solution of (S)-2-((tert- butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (1.00 g, 3.32 mmol), 4-methoxy-N-methylaniline (0.455 g, 3.32 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.64 mmol) in DMF (35 mL) and the reaction mixture was stirred at rt ON. The reaction was concentrated under high vacuum to afford the title compound (1.39 g) as a viscous oil. LC-MS retention time = 3.95 min; m/z = 443.11 [M+Na]+; (Column: Phenomenex Luna C18 50 x 2.0 mm 3 muetaiota. Solvent A = 90% Water : 10% MeOH : 0.1% TFA. Solvent B = 10% Water : 90% MeOH : 0.1% TFA. Flow Rate = 0.8 mL/min. Start % B = 0. Final % B = 100. Gradient Time = 4 minutes, then a 1-minute hold at 100% B. Oven temperature = 40 C. Wavelength = 220 nm). 1H NMR (400MHz, DMSO-d6) delta 7.30 (d, J=8.8 Hz, 2H), 7.16 - 6.95 (m, 4H), 6.42 (d, J=6.5 Hz, 2H), 4.17 - 4.09 (m, 1H), 3.80 (s, 3H), 2.79 - 2.73 (m, 1H), 2.64 (dd, J=13.3, 10.5 Hz, 1H), 1.28 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 15h; Inert atmosphere; | Typical procedure for the preparation of 1a General procedure: A solution of diphenylacetic acid (212 mg, 1.0 mmol), N-methylaniline (128 mg, 1.2mmol), DCC (247 mg, 1.2 mmol), and DMAP (24 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) was stirred at room temperature for 15 h. After aqueous extractive workup and column chromatographic purification process (hexanes/Et2O,5:1) 1a was obtained as a white solid, 226 mg (75%). Other 2,2,N-triarylacetamides were prepared similarly from corresponding N-arylaminesand 2,2-diarylacetic acids. Diphenylacetic acid, bis(4-chlorophenyl)acetic acid and 9-fluorenecarboxylic acid were purchased from commercial sources, and other diarylacetic acids were prepared by Friedel-Crafts reaction of arenes and corresponding mandelic acid derivatives according to the reported methods.3,4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With hydrogenchloride; In water; butan-1-ol; at 150℃; for 4h; | Dichloropyrimidine (compound 9, Scheme 1E) was subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of i-PrOH to afford compound 2, Section E. Compound 2, section E., was hydrogenated under Pd/C at 50 psi for 3 hours (h) to afford compound 3, Section E. The synthesis of compounds 4 and 5, Section E., used trialkylaluminium in the presence of Pd catalyst and THF under reflux conditions. Compound 7, Section E., was obtained from 2 using aqueous hydriodic acid at 0 C-rt. Compound 7 was then heated at 120 C in the presence of DMF and copper cyanide to yield compound 8, Section E. One of the chloro groups of compound 9, Section E, was substituted with the amino group under SNAr conditions with ethanolic ammonia to produce compound 10, Section E., which was then subjected to nucleophilic displacement with 4-methoxy-N-methylaniline and a catalytic amount of concentrated HC1 in the presence of butanol to afford compound 6, Section E. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | [00229j SOC12 (2 mL) was added to a solution of 1,2,3,4-tetrahydro-naphthalene-1- carboxylic acid (0.6 g, 3.4 mmol) in DCM (10 mL) and the mixture was refluxed for 2h. The solvent was concentrated and the residue was added to a mixture of (4-methoxy-phenyl)-methyl- amine (470 mg, 3.4 mmol) and TEA (2 mL) in DCM (10 mL). The reaction mixture was stirred at RT for 5h and quenched with iN HC1 (10 mL). The organic layer was separated, washed with water, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE:EA, 4:1) to give 630 mg (63%) of the title compound. [M+H] Calc?d for C19H21N02, 296; Found, 296. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3 mg; 44 mg | With Rh2(esp)2; acetic acid; In 2,2,2-trifluoroethanol; at 0℃; for 0.33h;Inert atmosphere; | Following the general intermolecular amination procedure, anisole (7f: 54 mg, 0.5 mmol), Du Bois' catalyst (7.6 mg, 0.01 mmol), and TsONHMe (0.151 g, 0.75 mmol) were stirred at 0 C. in a mixture of TFE/AcOH (4:1, 5 mL) for 0.33 h. The reaction was basified with aqueous 1.0 M NaOH. Chromatographic purification of the crude product afforded 8f (44 mg) and 8g (3 mg) as oils (69% combined yield) whose spectral data were in agreement with literature values (44). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen; copper(II) acetate monohydrate In acetonitrile at 100℃; for 16h; Schlenk technique; | |
13% | With disodium hydrogenphosphate; potassium dihydrogenphosphate at 30℃; for 18h; Microbiological reaction; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In toluene; at 25℃; for 3.5h;Inert atmosphere; | General procedure: To a stirred solution of <strong>[4316-93-2]4,6-dichloro-5-nitropyrimidine</strong> (1.5mmol), amine (0.5mmol), Pd2(dba)3 (0.01mmol), R-BINAP (0.03mmol) and potassium carbonate (0.7mmol) in toluene (5mL) at room temperature and the mixture was under an argon atmosphere for 3.5h. The resulting reaction mixture was filtered and evaporated. The residue was purified by column chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.6% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; In acetonitrile; at 25℃; for 3.5h;Inert atmosphere; | General procedure: 6-Chloro-5-nitropyrimidine-4-amine (0.5mmol), amine (1.5mmol), Pd2(dba)3 (0.01mmol), R-BINAP (0.03mmol) and potassium carbonate (0.7mmol) were dissolved in acetonitrile (5mL). The solution was stirred at room temperature for 3.5h under an argon atmosphere. The resulting reaction mixture was treated with saturated brines (50mL) and extracted with acetonitrile (3×25mL), and dried with anhydrous Na2SO4. The anhydrous Na2SO4 was removed by filtration and the filtrate was concentrated. The residue was washed with ethyl acetate (3×2mL) and diethyl ether (3×2mL), filtered and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With hydrogenchloride; In butan-1-ol; for 72h;Reflux; | General procedure: To a 100 mL round bottom flask were added appropriate 4-chloro-pyrimido[4,5-b]indole 11 or 12 (1 equivalent), 4-methoxy-N-methylaniline (4 equivalents), conc. HCl (2 drops), and BuOH (25 mL). The reaction mixture was heated to reflux for 72 h. After cooling to rt, silica gel (500 mg) was added, and BuOH was removed under reduced pressure to afford a silica gel plug. The plug was transferred on top of a column packed with silica gel, 20 times the weight of plug, and was eluted with 0.5% and 1% MeOH in CHCl3. Fractions containing the product (TLC) were pooled, and the solvent was evaporated to afford target compounds 2 or 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 80℃; | General procedure: 6-chloro-9-H-purines (0.5 mmol), isopropanol (3 mL) and 4-methoxy-N-methylaniline (82 mg, 0.6 mmol) was added into around flask (5 mL) with a stir bar. The resulting mixture was stirredat 80 C until the starting material disappeared on TLC. Then thesolvent was removed under reduced pressure to afford crudeproduct, which was purified by chromatography on silica gel (petroleumether/acetic ether 1: 1, v/v) to get target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In isopropyl alcohol; at 80℃; | General procedure: 6-chloro-9-H-purines (0.5 mmol), isopropanol (3 mL) and 4-methoxy-N-methylaniline (82 mg, 0.6 mmol) was added into around flask (5 mL) with a stir bar. The resulting mixture was stirredat 80 C until the starting material disappeared on TLC. Then thesolvent was removed under reduced pressure to afford crudeproduct, which was purified by chromatography on silica gel (petroleumether/acetic ether 1: 1, v/v) to get target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 12h;Inert atmosphere; | To a stirred solution of 4-methoxy-N-methylaniline ([5961-59-1], 3.6 g, 26.27 mmol) and <strong>[18442-22-3]7-bromochroman-4-one</strong> ([18442-22-3], 7.15 g, 31.53 mmol) in toluene (40 mL) were added Cs2C03 (17.07 g, 52.54 mmol), BINAP (1.31 g, 2.10 mmol) and Pd(OAc)2 (0.47 g, 2.10 mmol). The reaction was stirred at 100 C for 12 h under inert atmosphere. The mixture was partitioned between water and EtOAc. The organic layer was concentrated and purified by silica-gel column chromatography [gradient elution with 10% EtOAc in Hexane] to afford the target compound (2.9 g, 40.0%) as a brown solid. LCMS MH+ calculated, 284.1, found, 284.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; In water; isopropyl alcohol; at 20.0℃; | To a solution of <strong>[1321618-96-5]4-chloro-5-methylfuro[2,3-d]pyrimidine</strong> (12, 85 mg, 0.5 mmol) and 4-methoxy-N-methylaniline (5, 80 mg, 5.75 mmol) in 2 mL of anhydrous isopropanol (IPA) added 2 drops of concentrated HC1 and the reaction mixture was stirred at room temperature overnight. The brown precipitate was collected by filtration, washed with cold isopropanol, and dried under vacuum to afford compound 2 (95 mg, 75 %) as brown solid. Analytical data of compound 2 is identical with the product obtained using previous method.12 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.6% | With hydrogenchloride; In water; isopropyl alcohol; at 20℃; | Intermediate 10 was synthesized according the procedures reportedin the previous literature [26]. To a solution of 10 (3.62 g, 0.015 mol)and N-methyl-4-methoxyaniline (2.31 g, 0.017 mol) in 25 mL of anhydrousisopropanol (IPA) was added 0.6 mL of concentrated HCl, and themixture was stirred at room temperature overnight. The mixture wasextracted with CH2Cl2 (3×50 mL). The combined organic layers werethen washed with brine, dried over anhydrous Na2SO4, and concentratedin vacuo to afford crude product 11 (4.2 g, 81.6%) as yellowsolid. To a solution of 11 (4.2 g, 0.012 mol) in 20 mL CH3OH was added20 mL 10% NaOH aqueous, and the mixture was stirred at 80 C for 2 h.The CH3OH was then removed in vacuo and acidized with 10% HClaqueous to pH 3. The yellow precipitates were collected by filtration,washed with water and dried to afford intermediate 12 (2.9 g, 76.3%)as yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1 g | Stage #1: N-methyl-N-(4-methoxyphenyl)amine With sodium hydride In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 3-chlorobenzo[b]thiophen-2-carbonyl chloride In tetrahydrofuran at 20℃; for 24h; Darkness; | 19 3-Chloro-N-(4-methoxyphenyl)-N-methylbenzo[b]thiophene-2-carboxamide (14b) To a solution of 3-chlorobenzo[b]thiophene-2-carboxylic acid (0.70 g, 3.5 mmol) in anhyd benzene (20 mL) was added 5 mL thionyl chloride (8.2 g, 64 mmol), and the reaction was refluxed for 12 h. After concentrating in vacuo the acid chloride product was used in the next synthesis without further purification. To a solution of 4-methoxy-N-methylaniline (0.43 g, 3.2 mmol) in anhyd THF (10 mL) was slowly added 60% NaH (0.20 g, 5.0 mmol) followed by stirring for 20 min under nitrogen at room temperature. The above acid chloride was then added slowly in portions with stirring. The reaction mixture was stirred in the dark for 24 h at room temperature, and DCM (50 mL) was added. The reaction mixture was filtered and concentrated in vacuo to give a dark oil. Column chromatography of the oil, eluting with ethyl acetate in hexane (2:8, v/v) and washed with cold hexane, gave amide 14b (1.0 g, 88% yield) as a colorless solid, mp 126-127 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.35 (m, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 3.69 (s, 3H), 3.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ. 162.8, 158.5, 137.6, 135.6, 135.4, 130.7, 127.8, 126.2, 124.9, 122.4, 122.4, 120.4, 114.2, 55.2, 38.2. HRMS: (ESI/IT-TOF) m/z: [M+H]+ calcd for C17H15NO2SCl 332.0507, found 332.0474. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | With hydrogen; sodium hydroxide In methanol at 125℃; for 4h; Autoclave; | 1; 6 Example 1 Effect of aldehyde on the reaction Add p-nitroanisole, aldehyde, NaOH, Raney nickel and methanol to the autoclave, seal the reaction dad, replace the air in the autoclave with hydrogen for 5 times, and then react at a hydrogen pressure of 3.5 MPa and a temperature of 125 °C. 4 hours,The catalyst was filtered off by cooling, and the filtrate was distilled to remove the solvent to obtain N-methyl p-aminoanisole.The molar equivalent ratio of the raw materials and the results are shown in Table 2. Note: 1) 1, 3, 6 added aldehyde is formaldehyde, 2, 4, 5 added paraformaldehyde. 2) Product 1 methyl p-aminoanisoleThe molecular structure was confirmed by the 1 NMR spectrum of Figure 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 2 mmol of trifluoroethylamine hydrochloride was added to the reaction tube.1 mL of water, 34 uL of acetic acid, 1 mL of dichloroethane, covered with a rubber stopper, and fixed on a stirrer. Take 42 mg of sodium nitrite in a 1.5 mL sample tube, add 1 mL of water to the sample tube, and shake the sample. the tube is dissolved in sodium nitrite. dissolving the dissolved sodium nitrite solution into the reaction tube with a syringe, Stir for half an hour at room temperature. dissolving the iron porphyrin of Formula 3 with 1 mL of dichloromethane (R2 = R3 = H, R1 = Cl, L = Cl) (catalytic amount, is 9/1000 of the molar amount of secondary amine, take 0.24mmol 4-methoxy-N-methylaniline was placed in the sample tube. After half an hour, the mixed solution in the sample tube was dropped into the reaction tube, stirred while stirring, and the temperature was raised to 80 C for 12 hours. The reaction solution was cooled to room temperature and filteredPart of the impurities were removed, concentrated and purified by column chromatography to obtain the desired product. The column chromatography eluent was a mixed solvent of petroleum ether and acetone. The structure of 4-methoxy-N-methyl-N-(2,2,2-trifluoroethyl)aniline is as follows: The compound is a pale yellow liquid with a yield of 75% and its nuclear magnetic data is as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,4-diaza-bicyclo[2.2.2]octane; 1,3-dicyano-5-fluoro-2,4,6-tris(diphenylamino)benzene In acetonitrile at 20℃; for 12h; Inert atmosphere; Irradiation; |
Tags: 5961-59-1 synthesis path| 5961-59-1 SDS| 5961-59-1 COA| 5961-59-1 purity| 5961-59-1 application| 5961-59-1 NMR| 5961-59-1 COA| 5961-59-1 structure
[ 20440-94-2 ]
4-Methoxy-N-(4-methoxyphenyl)-N-phenylaniline
Similarity: 0.88
[ 20440-94-2 ]
4-Methoxy-N-(4-methoxyphenyl)-N-phenylaniline
Similarity: 0.88
[ 20440-94-2 ]
4-Methoxy-N-(4-methoxyphenyl)-N-phenylaniline
Similarity: 0.88
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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 |
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