Reaction Steps
To a solution of 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbonitrile (Example 84, 590 mg, 2.4 mmol) in toluene (20 mL) at −60° C. is added a 1 M solution of DIBAL-H (3.6 mL, 3.6 mmol). The reaction is stirred for 1 h and kept below −40° C. The reaction is then quenched with water (1 mL) and brought to room temperature. Anhydrous sodium sulfate (ca. 2 g) is then added to the reaction mixture. The reaction mixture is filtered through a plug of celite. Sulfuric acid (2M, ca. 5 mL) is added and upon complete conversion to the desired aldehyde, the reaction mixture is brought to pH 8 with the addition of Na2CO3, and extracted with ethyl acetate. The organic extract is washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde is used without further purification. To a solution of ethoxymethyltriphenylphosphonium chloride (0.32 g, 0.9 mmol) in THF (3 mL) is added potassium tert-butoxide (1 M in THF, 0.93 mL, 0.93 mmol). The resulting red solution is permitted to stir for 15 min, at which time a solution of 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde (75 mg, 0.3 mmol) in THF (3 mL) is added. The reaction is stirred for 1 h, quenched with saturated aqueous NH4Cl, diluted with water and extracted with ethyl acetate. The organic extract is dried over Na2SO4, filtered, and concentrated. The resulting E/Z mixture of 3-(2-ethoxy-vinyl)-1-ethyl-2-pyridin-3-yl-1H-indole is then dissolved in methanol (5 mL) and 10% Pd/C (32 mg, 0.03 mmol) is added. The reaction mixture is stirred under an atmosphere of H2 gas (balloon) for 2 h. The reaction is then filtered through a plug of celite and concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 2:5) to afford 3-(2-ethoxy-ethyl)-1-ethyl-2-pyridin-3-yl-1H-indole. 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (t, J=7.0 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H), 2.94 (t, J=7.3 Hz, 2H), 3.43 (q, J=7.1 Hz, 2H), 3.61 (t, J=7.3 Hz, 2H), 4.05 (q, J=7.3 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.30 (t, J=7.1 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.53 (dd, J=7.6, 5.1 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.72 (dd, J=4.9, 1.6 Hz, 1H), 8.77 (d, J=1.5 Hz, 1H). HRMS (ESI) m/z 295.1805 [(M+H)+ Calcd for C19H23N2O: 295.1810].
