92% |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Ethyl 3-(phenethylcarbamoyl)propylcarbamate (santacruzamate A. 1):
General procedure: 4- ((ethoxycarbonyl)amino)butanoic acid (0.40 g, 2.28 mmol) was dissolved in CH2CI2 (7 mL) and cooled to 0 °C. Phenethylamine (0.327 mL, 2.60 mmol) and triethylamine (0.64 mL, 4.56 mmol) were added to the solution followed by l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.50 g, 2.60 mmol) in one portion. 4-Dimethylaminopyridine (catalytic (cat.)) was added and the solution was stirred at 0 °C for 60 min, then overnight at room temperature. The resulting solution was diluted with additional CH2CI2 (20 mL) and washed sequentially with 10 mL of each of the following: 1.0 M HC1, sat. NaHCC^, H20, brine. The organic layer was dried over Na2S04 and concentrated to give a residue that was recrystallized by trituration with hexanes. Upon cooling to 0 °C the solution was filtered to yield 1, which was obtained as a white solid (0.58 g, 92 % yield): mp 112-113 °C; IR vmax (film) 3345, 3288, 1703, 1699, 1655, 1543, 1538, 1446, 1307, 1285, 1249, 1223, 1139, 1050, 1031; lR NMR (500 MHz, CDC13) 5 7.30-7.36 (m, 2H), 7.20-7.28 (m, 3H), 5.96 (br s, 1H), 4.96 (br s, 1H), 4.12 (q, J= 6.94 Hz, 2H), 3.55 (q, J= 6.73 Hz, 2H), 3.20 (q, J= 5.88 Hz, 2H), 2.85 (t, J= 6.94 Hz, 2H), 2.20 (t, J= 6.94 Hz, 2H), 1.82 (pentet, J= 6.78 Hz, 2H), 1.25 (t, J= 7.25 Hz, 3H); 13C NMR (126 MHz, CDCI3) δ 172.5, 157.1, 138.9, 128.8, 128.6, 126.5, 60.8, 40.6, 40.2, 35.7, 33.7, 26.1, 14.7; ESI-MS m/z (%) 301.1 (8, [M+Na]+), 280.2 (25) 279.3 (100, [M+H]+); HRESI-MS [M+H]+ m/z 279.1726 (calculated for Ci5H23N203, |
70% |
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In tetrahydrofuran at 0 - 20℃; for 14.25h; Inert atmosphere; |
2 1.1 Ethyl (4-oxo-4-(phenethylamino)butyl)carbamate, 5a (Santacruzamate-A)
In a round bottom flask oven dried, to a dry THF solution (3.6 mL) of 11 (50 mg, 0.28 mmol) phenylethylamine (70 mg, 0.57 mmol, 72 μL) was added dropwise and the reaction mixture was stirred under dry N2 atmosphere at 0 °C for 15 min. After that period, NMM (1.26 mmol, 139 μL) and DMTMM (140 mg, 0.50 mmol) were added and the mixture allowed to reach room temperature up to 14h. The crude mixture was washed twice with Na2CO3ss and the aqueous phase extracted with EtOAc. The collected organic phases were then washed twice with NH4Clss and then extracted with EtOAc. The collected organic phases were washed twice with NaClss and then extracted with EtOAc. The final collected organic phases were dried under Na2SO4 and then filtered; and solvent evaporated in vacuo. The crude mixture was purified by column chromatography (DCM/MeOH 9:1) to afford compound 5a as white solid (55 mg, 70%). Experimental data are in agreement to those reported in literature.1 1H NMR (300 MHz, Methanol-d4) δ 7.35 - 7.14 (m, 5H), 4.06 (q, J = 7.0 Hz, 2H), 3.40 (t, J = 7.3 Hz, 2H), 3.07 (t, J = 6.9 Hz, 2H), 2.79 (t, J = 7.3 Hz, 2H), 2.16 (t, J = 7.5 Hz, 2H), 1.73 (p, J = 7.1 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H) ppm. 13C NMR (75 MHz, MeOD) δ: 176.27, 159.88, 141.09, 130.32, 129.98, 127.84, 127.80, 61.73, 41.92, 41.07, 36.43, 34.22, 27.18 ppm. HRMS (ESI-Q-TOF) m/z [M+H]+ Calcd. for C15H23N2O3 279.1703; Found 279.1714 |