Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.
Procedure: A stirred solution of 4-[2-(dimethylamino)ethoxy]aniline [R Paul et al, J. Med. Chem. 36, 1993, 2716-2725](3.61 g, 20 mmol) in water (34 mL) and concentrated HCl (10 mL) was diazotized at 0° C. with a solution of NaNO2 (1.52 g, 22 mmol) in water (4 mL). The cold solution was added in one portion to a vigorously stirred ice-cold mixture of ethyl 2-methylacetoacetate (3.03 g, 21 mmol), anhydrous NaOAc (17 g), EtOH (25 mL), and freshly added ice (20 g). After stirring at 20° C. for 1 h, the mixture was cooled to 0° C., basified by the slow addition of solid Na2CO3, and extracted immediately with CH2Cl2 (×2). The combined organic layers were washed with water, dried (Na2SO4), and evaporated. The residue was extracted with hot petroleum ether (bp 60-65° C.) in the presence of decolorizing charcoal, and the clarified solution was evaporated. The remaining oil (4.55 g) was dissolved in absolute EtOH (6 mL) and HCl-saturated EtOH (10 mL) was added. After heating at reflux for 25 min, the solution was concentrated and the residue was partitioned between dilute Na2CO3 and CH2Cl2. The organic layer was washed with water and NaCl solution, dried, and evaporated. The residue was triturated with iPr2O/hexanes and the resulting solid was recrystallized from iPr2O/hexanes to give ethyl 5-[2-(dimethylamino)ethoxy]indole-2-carboxylate (1.32 g, 24% overall yield) as needles, mp 110° C. 1H NMR [(CD3)2SO] δ 11.72 (s, 1 H, NH), 7.34 (d, J=9.0 Hz, 1 H, H-7), 712 (d, J=2.4 Hz, 1 H, H-4), 7.03 (d, J=1.6 Hz, 1 H, H-3), 6.91 (dd, J=9.0, 2.4 Hz, 1 H, H-6), 4.32 (q, J=7.1 Hz, 2 H, CH2CH3), 4.03 (t, J=5.9 Hz, 2 H, OCH2), 2.63 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.22 (s, 6 H, N(CH3)2), 1.33 (t, J=7.1 Hz, 3 H, CH2CH3).
the mixture was cooled to 0° C.
extracted immediately with CH2Cl2 (×2)
The combined organic layers were washed with water
dried (Na2SO4)
evaporated
The residue was extracted with hot petroleum ether (bp 60-65° C.) in the presence of decolorizing charcoal
the clarified solution was evaporated
The remaining oil (4.55 g) was dissolved in absolute EtOH (6 mL)
HCl-saturated EtOH (10 mL) was added
After heating
at reflux for 25 min
the solution was concentrated
the residue was partitioned between dilute Na2CO3 and CH2Cl2
The organic layer was washed with water and NaCl solution
dried
evaporated
The residue was triturated with iPr2O/hexanes
the resulting solid was recrystallized from iPr2O/hexanes
Source ID: ord-4d896c711dfe465b8ca63f78b1d61108