反应详情

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].

1. customkept below −40° C
2. customThe reaction is then quenched with water (1 mL)
3. custombrought to room temperature
4. additionAnhydrous sodium sulfate (ca. 2 g) is then added to the reaction mixture
5. filtrationThe reaction mixture is filtered through a plug of celite
6. additionSulfuric acid (2M, ca. 5 mL) is added and upon complete conversion to the desired aldehyde
7. additionthe reaction mixture is brought to pH 8 with the addition of Na2CO3
8. extractionextracted with ethyl acetate
9. extractionThe organic extract
10. washis washed with brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated
14. customThe resulting 1-ethyl-2-pyridin-3-yl-1H-indole-3-carbaldehyde is used without further purification
15. additionis added
16. stirringThe reaction is stirred for 1 h
17. customquenched with saturated aqueous NH4Cl
18. additiondiluted with water
19. extractionextracted with ethyl acetate
20. extractionThe organic extract
21. dry with materialis dried over Na2SO4
22. filtrationfiltered
23. concentrationconcentrated
24. additionThe resulting E/Z mixture of 3-(2-ethoxy-vinyl)-1-ethyl-2-pyridin-3-yl-1H-indole
25. dissolutionis then dissolved in methanol (5 mL)
26. stirringThe reaction mixture is stirred under an atmosphere of H2 gas (balloon) for 2 h
27. filtrationThe reaction is then filtered through a plug of celite and
28. concentrationconcentrated to dryness
29. customThe resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 2:5)