N-(Phenylmethyl)-β-alanine ethyl ester

Solid

General procedure: The amine (7.5 mmol) and the Michael acceptor (5 mmol) in a molar ratio of 1.5:1 were refluxedwith stirring in the presence of acidic alumina (1 g, 200 molpercent). Heating was performed using an oilbath and the reaction was followed by TLC and GC until completion. The reaction was then allowedto cool down to room temperature and filtered through a filter paper. The catalyst was rinsed withethyl acetate/hexane and then concentrated by rotary evaporation. The crude reaction mixture waspurified using a silica-filled chromatographic column using hexane/ethyl acetate as eluents. Usually, for aliphatic amines, the mono-adduct was eluted using 7:3, 6:4 or 5:5 hexane/ethyl acetate whilstfor aromatic ones the solvent mixture used was 8:2 hexane/ethyl acetate. The yields of the purifiedproducts were recorded and then IR and NMR spectroscopy and MS spectrometry were performed.General procedure: The catalytic liquid-phase reaction was performed in a two necked round bottom flask with a water condenser under vigorously stirring condition. General procedure: To a Schlenk line sealed tube charged with amine (1mmol), α, β-unsaturated compound (1.2mmol) in 4ml of dry toluene, MIL-100(Fe) (3molpercent) was added under stirring condition.The mixture was then stirred for a certain time at 50°C.The progress of reaction was monitored by TLC. After completionof the reaction, the catalyst was completely recoveredfrom the residue by centrifuge, and the product was extractedfrom reaction mixture with ethyl acetate and H2O/2M HCl. The organic phase was evaporated under reduced pressureand the reaction mixture was then subjected to column chromatography(n-hexane:ethyl acetate = 4:1, V/V) to give thecorresponding aza-Michael products. All products and characterizedby comparison of their physical properties, 1H and13C spectra with those of already reported [17, 39, 40].To ethyl acrylate (100 g, 1.00 mol) Diazabicycloundecene (DB U, 7.6 g, 0.05 mol) was added dropwise so that the temperature in the reaction system was maintained at 10 ° C. or lower. Then, benzylamine (108.7 g, 1.01 mol) was added dropwise so that the temperature in the reaction system was maintained at 10 ° C. or lower. Thereafter, the temperature was raised to room temperature (23 ° C.) over 1 hour and then stirred at room temperature for 4 hours. The obtained reaction product was purified by silica gel column chromatography (ethyl acetate / hexane: 10/1 → 3/1) To obtain N-benzyl-β-alanine ethyl ester (117 g, yield 56percent) as an oil.To a solution of benzylamine 3a (2.6 g, 24.0 mmol) in HAt room temperature, 10g (0.1mol) of ethyl acrylate was slowly added dropwise 10.7g (0.1mol) benzylamine in ethanol solution. Maintaining the reaction, it was stirred at room temperature for 10 hours. Distilled under reduced pressure gave 20.5g pale yellow oil. Was used directly without purification in the next step.General procedure: The amine (7.5 mmol) and the Michael acceptor (5 mmol) in a molar ratio of 1.5:1 were refluxedwith stirring in the presence of acidic alumina (1 g, 200 mol%). Heating was performed using an oilbath and the reaction was followed by TLC and GC until completion. The reaction was then allowedto cool down to room temperature and filtered through a filter paper. The catalyst was rinsed withethyl acetate/hexane and then concentrated by rotary evaporation. The crude reaction mixture waspurified using a silica-filled chromatographic column using hexane/ethyl acetate as eluents. Usually, for aliphatic amines, the mono-adduct was eluted using 7:3, 6:4 or 5:5 hexane/ethyl acetate whilstfor aromatic ones the solvent mixture used was 8:2 hexane/ethyl acetate. The yields of the purifiedproducts were recorded and then IR and NMR spectroscopy and MS spectrometry were performed.General procedure: The catalytic liquid-phase reaction was performed in a two necked round bottom flask with a water condenser under vigorously stirring condition. The catalyst was pre-activated at 393 K in an oven and subsequently used for the reactions. In a typical procedure, a mixture of piperidine (5 mmol) and ethyl acrylate (5 mmol) was added to a pre-activated catalyst (25 mg). The reaction mixture was stirred at room temperature for a period of 20 min. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the catalyst was separated by centrifugation. The filtrate was concentrated and corresponding product was purified through column chromatography using silica gel (100-200 mesh), petroleum ether:ethyl acetate (3:1The desired product 3-piperidin-1-yl-propionic acid ethyl ester was confirmed through 1H NMR and compared with reported literature [15]General procedure: To a Schlenk line sealed tube charged with amine (1mmol), alpha, beta-unsaturated compound (1.2mmol) in 4ml of dry toluene, MIL-100(Fe) (3mol%) was added under stirring condition.The mixture was then stirred for a certain time at 50C.The progress of reaction was monitored by TLC. After completionof the reaction, the catalyst was completely recoveredfrom the residue by centrifuge, and the product was extractedfrom reaction mixture with ethyl acetate and H2O/2M HCl. The organic phase was evaporated under reduced pressureand the reaction mixture was then subjected to column chromatography(n-hexane:ethyl acetate = 4:1, V/V) to give thecorresponding aza-Michael products. All products and characterizedby comparison of their physical properties, 1H and13C spectra with those of already reported [17, 39, 40].To ethyl acrylate (100 g, 1.00 mol) Diazabicycloundecene (DB U, 7.6 g, 0.05 mol) was added dropwise so that the temperature in the reaction system was maintained at 10 C. or lower. Then, benzylamine (108.7 g, 1.01 mol) was added dropwise so that the temperature in the reaction system was maintained at 10 C. or lower. Thereafter, the temperature was raised to room temperature (23 C.) over 1 hour and then stirred at room temperature for 4 hours. The obtained reaction product was purified by silica gel column chromatography (ethyl acetate / hexane: 10/1 ' 3/1) To obtain N-benzyl-beta-alanine ethyl ester (117 g, yield 56%) as an oil.To a solution of benzylamine 3a (2.6 g, 24.0 mmol) in H2O (100 mL) were added ethyl acrylate (2 g, 20.0 mmol), and Cu(OAc)2 (182 mg, 1.0 mmol). The resulting mixture was stirred at room temperature for 6 h. After termination of the reaction, the solution was extracted with EtOAc, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc = 1:1) to afford the desired product 4a (2.34 g, 11.3 mmol, 47% yield) as a yellow oil: 1H-NMR (300 MHz, CDCl3) delta 7.36-7.23 (m, 5H), 4.14 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 2.90 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 6.3 Hz, 2H), 1.66 (s, 1H), 1.25 (t, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3) delta 172.79, 140.17, 128.42, 128.09, 126.96, 60.41, 53.77, 44.51, 34.79, 14.23; LC/MS (ESI+): m/z: calcd for C12H17NO2: 207.27, [M+H]+; found: 208.00.Part C: Ethyl 3-(benzylamino)propionate. This compound is prepared according to the method of Klioze and Ehrgott (U.S. Pat. No. 4, 216, 218) from ethyl acrylate and benzylamineReference Ethyl 3-(benzylamino) Propionate 1 STR16 To a solution containing 13.9 g (129.84 mmol) of benzylamine in 30 ml of ethanol, 10 g (99.88 mmol) of ethyl acrylate was slowly dropped at 50 C. for 1 hour under stirring. After the dropping, the mixture was heated at 80 C. for 1 hour. After the reaction, the reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain a residue in the form of oil. By distilling the residue under reduced pressure, excess benzylamine was recovered as the initial fraction (50-60 C., 0.75 mmHg) and then the captioned compound was obtained as a colorless oil at 129-133 C. (0.75 mmHg). Yield: 17.4 g Yield: 84.2%; bp. 129-133 C. (0.75 mmHg); IR (liquid film method); nu max cm-1:1734. NMR (90 MHz, CDCl3); delta:1.26(3H, t, J=7.0 Hz), 1.70(1H, br s), 2.53(2H, t, J=5.8 Hz), 2.91(2H, t, J=5.8 Hz), 3.82(2H, s), 4.16(2H, q, J=7.0 Hz), 7.31 (5H, s). Mass(EI); m/z: 207(M+)Step 1: ethyl 3-benzylamino-propionate 25 g (0.23 mol) benzylamine and 21 g (0.21 mol) ethyl acrylate in 125 mL EtOH were stirred for 15 h at RT. Then the solvent was evaporated down and the crude product was used in the next step without further purification. Yield: 30 g (62% of theoretical) ESI-MS: m/z=208 (M+H)+ Rf: 0.5 (silica gel, EtOAc/PE 50%)Step 1: ethyl 3-benzylamino-propionate 25 g (0.23 mol) benzylamine and 21 g (0.21 mol) ethyl acrylate in 125 mL EtOH were stirred at RT for 15 h. Then the solvent was evaporated down and the crude product was used in the next step without further purification. Yield: 30 g (62% of theory) ESI-MS: m/z=208 (M+H)+At room temperature, 10g (0.1mol) of ethyl acrylate was slowly added dropwise 10.7g (0.1mol) benzylamine in ethanol solution. Maintaining the reaction, it was stirred at room temperature for 10 hours. Distilled under reduced pressure gave 20.5g pale yellow oil. Was used directly without purification in the next step.(1) Take a 150mL round bottom flask, Measure the amount of benzylamine in an amount of 30 mmol, 10mL of absolute ethanol, And an equivalent amount of ethyl acrylate, Stir at room temperature for 16 h. Weigh 1.0 times equivalent of benzylamine diethyl oxalate, And 1.5 times the equivalent of sodium ethoxide is added to the reaction liquid of the first step, Then, 10 mL of absolute ethanol was added, and the system was transferred to an oil bath at 90 C for reflux for 1 h. Post-treatment: vacuum drying the absolute ethanol in the reaction solution, After cooling to room temperature, add 70 mL of deionized water. Add concentrated hydrochloric acid to adjust the system pH = 1, At this time, the system was exothermic, so it was moved to an ice bath for cooling, at which time a yellow-white solid precipitated. The supernatant is decanted and dried to give the compound of formula 1-5.(a) Take a 150 mL round bottom flask, Measure 30 mmol of benzylamine 1-1, respectively.10 mL of absolute ethanol and 30 mmol of ethyl acrylate 1-2 were stirred at room temperature for 16 h.Weigh 30 mmol of diethyl oxalate 1-4, 45mmol sodium ethoxide was added to the reaction liquid of the first step, and 10 mL of absolute ethanol was added.The system was transferred to a 90 C oil bath and refluxed for 1 h.Post-treatment: vacuum drying the absolute ethanol in the reaction solution, After cooling to room temperature, add 70 mL of deionized water, and then add concentrated hydrochloric acid to adjust the system pH=1.At this time, the system was exothermic, so it was moved to an ice bath for cooling, at which time a yellow-white solid precipitated.The supernatant was poured and the resulting solid was dried to give compound 1-5.(1)Take a 150mL round bottom flask, measure 30mmol of benzylamine, 10mL of absolute ethanol, etc. Equivalent ethyl acrylate was stirred at room temperature for 16 h. Weigh 1.0 times equivalent of benzylamine diethyl oxalate and 1.5 times equivalent of sodium ethoxide to the reaction liquid of the first step, and add 10 mL of absolute ethanol, and transfer the system to an oil bath at 90 C for reflux. Reaction 1h. Post-treatment: vacuum dry the absolute ethanol in the reaction solution, cool to room temperature, add 70mL deionized water, then add concentrated hydrochloric acid to adjust the system pH=1, at this time the system is exothermic, so move to the ice bath to cool, at this time A yellowish white solid precipitated. The supernatant is decanted and dried to give the compound of formula 1-5.General procedure: Under the protection of argon, the cobalt complex represented by the catalyst formula 2 (1.1 mg, 0.0025 mmol, 0.5 mol %), Boronamine (24.9 mg, 0.8 mmol, 1.6 equiv), benzonitrile (0.5 mmol), The amine compound and hexafluoroisopropanol (2 mL) were sequentially added to a 25 mL shrek bottle containing a magnetic stirrer and reacted at 25C for 13 hours. After the reaction was completed, the reaction mixture was diluted with 5 mL of methanol. The solvent was removed under reduced pressure and the residue was separated by column chromatography on silica gel to give the asymmetric secondary amine compoundBy following the same procedure but using the corresponding amines instead of p-anisidine, the following ethyl N-substituted b-aminopropionates are obtained: ... ethyl N-(3, 4, 5-trichlorophenyl)-b-aminopropionate, ethyl N-(2, 4, 6-tribromophenyl)-b-aminopropionate, ethyl N-(2, 4, 5-tribromophenyl)-b-aminopropionate, ethyl N-(3, 4, 5-tribromophenyl)-b-aminopropionate, ethyl N-benzyl-b-aminopropionate, ethyl N-(2-methoxybenzyl)-b-aminopropionate, ethyl N-(3-methoxybenzyl)-b-aminopropionate, ethyl N-(4-methoxybenzyl)-b-aminopropionate, ...Ethyl 3-phenylmethylaminopropionate (7) (X=N--CH3) A solution of freshly distilled N-methylaniline (267.5 g, 2.50 mol) and glacial acetic acid (50 mL) was placed in a one liter, 3-necked flask equipped with a water cooled condenser (carrying a CaCl2 drying tube) and an addition funnel charged with ethyl acrylate (250 g, 2.50 mol). The flask was warmed on a steam bath and the ethyl acrylate was added dropwise over a 25 minute period. The resulting yellow solution was heated with occasional swirling for 17 hours during which time it turned deep red. This solution was washed with 5% NaHCO3 (4*75 mL) and then with brine (3*75 mL). During the first wash, an emulsion formed, and 50 mL of diethyl ether was added to destroy it. After drying (MgSO4) the solution, evaporation gave a red oil which was distilled to give 404.5 grams, (78.2%) of compound 7 (X=N--CH3) as a yellow oil: bp 105-109 C./0.2 mm (literature report 98-100 C./0.05 mm; see D. W. Adamson, J. Chem. Soc. (Supplement I) S-144 (1949)): IR (neat) 1740 (C=O) cm-1; 1 H NMR (DCCl3) delta 1.15 [t, 3H, OCH2 CH3 ], 2.46 [t, 2H, CH2 CO2 CH3, J=7.08 Hz], 2.80 [s, 3H, NCH3 ], 3.59 [t, 2H, NCH2, J=7.08 Hz], 4.04 [q, 2H, OCH2 CH3 ], 6.67 [m, 3H, o & p--ArH], 7.18 [m, 2H, m--ArH]; 13 C NMR (DCCl3) ppm 14.1 [OCH2 CH3 ], 31.6 [C(2)], 37.9 [C(4)], 48.4 [C(3)], 60.2 [OCH2 ], 112.3 [C(6, 10)], 116.5 [C(8)], 129.0 [C(7, 9)], 148.4 [C(5)], 171.7 [C(1)]; Mass spectral data for C12 H17 NO2: m/e (M+) 207.1259; Found: 207.1261.(1) Take a 150mL round bottom flask, Measure the amount of benzylamine in an amount of 30 mmol, 10mL of absolute ethanol, And an equivalent amount of ethyl acrylate, Stir at room temperature for 16 h. Weigh 1.0 times equivalent of benzylamine diethyl oxalate, And 1.5 times the equivalent of sodium ethoxide is added to the reaction liquid of the first step, Then, 10 mL of absolute ethanol was added, and the system was transferred to an oil bath at 90 C for reflux for 1 h. Post-treatment: vacuum drying the absolute ethanol in the reaction solution, After cooling to room temperature, add 70 mL of deionized water. Add concentrated hydrochloric acid to adjust the system pH = 1, At this time, the system was exothermic, so it was moved to an ice bath for cooling, at which time a yellow-white solid precipitated. The supernatant is decanted and dried to give the compound of formula 1-5.(a) Take a 150 mL round bottom flask, Measure 30 mmol of benzylamine 1-1, respectively.10 mL of absolute ethanol and 30 mmol of ethyl acrylate 1-2 were stirred at room temperature for 16 h.Weigh 30 mmol of diethyl oxalate 1-4, 45mmol sodium ethoxide was added to the reaction liquid of the first step, and 10 mL of absolute ethanol was added.The system was transferred to a 90 C oil bath and refluxed for 1 h.Post-treatment: vacuum drying the absolute ethanol in the reaction solution, After cooling to room temperature, add 70 mL of deionized water, and then add concentrated hydrochloric acid to adjust the system pH=1.At this time, the system was exothermic, so it was moved to an ice bath for cooling, at which time a yellow-white solid precipitated.The supernatant was poured and the resulting solid was dried to give compound 1-5.(1) Take a 150mL round bottom flask, measure 30mmol of benzylamine, 10mL of absolute ethanol, etc.Equivalent ethyl acrylate was stirred at room temperature for 16 h.Weigh 1.0 times equivalent of benzylamine diethyl oxalate, 1.5 times equivalent of sodium ethoxide was added to the reaction liquid of the first step, and 10 mL of absolute ethanol was added thereto, and the system was transferred to an oil bath at 90 C for refluxing for 1 hour. Post-treatment: vacuum dry the absolute ethanol in the reaction solution, cool to room temperature, add 70mL deionized water, then add concentrated hydrochloric acid to adjust the system pH=1, at this time the system is exothermic, so move to the ice bath to cool, at this time A yellowish white solid precipitated. The supernatant is decanted and dried to give the compound of formula 1-5.

Molecular Weight:207.27
XLogP3:1.5
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:7
Exact Mass:207.125928785
Monoisotopic Mass:207.125928785
Topological Polar Surface Area:38.3
Heavy Atom Count:15
Complexity:177
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes