Reaction Steps
A benzene (15 mL) solution of ethyl-4-[(tert-butoxycarbonyl)(methyl)amino]-3-oxobutanoate (1.80 g, 6.31 mmol), 2-formyl-1,3-thiazole-5-carboxylic acid (0.992 g, 6.31 mmol) and piperidine (0.312 mL, 3.16 mmol) was refluxed with azeotropic removal of H2O for 1.5 h and then cooled to ambient temperature and concentrated. The residue was redissolved in EtOAc and washed with 1 N HCl, 2× H2O, 1× brine and the organics dried (Na2SO4), filtered and concentrated to an amorphous brown solid. The Knoevenagel product (2.68 g, 6.31 mmol) and ethyl (2Z)-3-amino-4-(4-fluorophenyl)-2-butenoate (1.41 g, 6.31 mmol) were heated to 110° C. for 2 h and then cooled to ambient temperature. The glassy dihydropyridine solid (0.200 g, 0.318 mmol) was redissolved in CH2Cl2 (2 mL). R-(−)-1-aminoindane (0.041 mL, 0.476 mmol) was added followed by EDCI (0.073 g, 0.381 mmol) and HOBt (0.052 g, 0.381 mmol). After 14 h of stirring at ambient temperature the reaction mixture was poured onto 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. The residue was redissolved in CH3CN (2 mL) and H2O (2 mL) followed by addition of ceric ammonium nitrate (0.348 g, 0.635 mmol). The reaction mixture stirred for 45 min at ambient temperature and then Et2O was added and the organics extracted and washed 1× H2O, 1× brine, and then dried (Na2SO4), filtered and concentrated to a dark brown solid. The solid was subjected to TFA (6 mL in 3 mL CH2Cl2) for 1 h and then concentrated. The residue was redissolved in CH2Cl2 (15 mL) and treated with Et3N (5 mL). After 16 h the reaction mixture was concentrated to a brown foam. The residue was redissolved in EtOAc and washed with 5% HCl solution and extracted with CH2Cl2. The organics were washed with sat'd NaHCO3, brine and then dried (Na2SO4), filtered and concentrated to a brown residue. Chromatography on silica gel using 2:1 EtOAc:Hexanes eluted the title compound (0.011 g, 0.018 mmol, 6% yield based upon dihydropyridine used in the amide coupling) after concentration as an off-white solid. 1H NMR (CDCl3, 400MHz) δ 8.26 (s, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.26–7.13 (m, 5H), 6.91 (t, J=8.7 Hz, 2H), 6.24–6.14 (m, 1H), 5.64 (dd, J=14.8, 7.4 Hz, 1H), 4.71 (dd, J=10.2, 6.3 Hz, 1H), 4.27 (d, J=14.6 Hz, 2H), 4.07 (dd, J=14.1, 7.0 Hz, 2H), 3.78–3.68 (m, 1H), 3.44–3.38 (m, 1H), 3.10–2.99 (m, 1H), 2.94–2.86 (m, 1H), 2.70–2.62 (m, 1H), 2.48–2.40 (m, 1H), 2.37–2.25 (m, 2H), 1.96–1.86 (m, 1H), 1.42–1.35 (m, 1H), 1.13 (t, J=7.1 Hz, 3H); ESMS m/z 597 (M+H)+, 595 (M−H)+.
