Pyrrolidine → 4-(Trifluoromethyl)-1H-indole

Temperature

60 °C

A solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (10.00 g, 48.8 mmol), pyrrolidine (4.44 mL, 53.7 mmol) and dimethylformamide dimethylacetal (19.8 mL, 146 mmol) in DMF (100 mL) was heated at 100° C. for 4 h, cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in THF/MeOH (1:1, 200 mL), and transferred to a 3-necked flask equipped with an overhead stirrer, reflux condenser, and dropping addition funnel. Raney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion and the entire apparatus was thoroughly flushed with N2. The mixture was heated to 60° C., under N2, and a solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h. The mixture was heated at 60° C. for 1 h, cooled, and filtered through a pad of Celite®. The filtrate was concentrated in vacuo, the residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×3). Combined organics were washed (10% HCl, H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 5.17 g of the title compound as a light brown liquid: 1H NMR (300 MHz, methanol-d4) δ 7.61 (d, J=8.2 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.19 (partially resolved dd, J 8.4, 7.5 Hz, 1H), 6.59 (br. s, 1H).

1. temperaturecooled
2. concentrationconcentrated in vacuo
3. customThe residue was partitioned between Et2O/H2O
4. customthe layers were separated
5. extractionthe aqueous layer was extracted with Et2O (×3)
6. washCombined organics were washed (H2O, brine)
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. dissolutionThe residue was dissolved in THF/MeOH (1:1, 200 mL)
11. customtransferred to a 3-necked flask
12. customequipped with an overhead stirrer
13. temperaturereflux condenser
14. additionaddition funnel
15. additionRaney-Ni (Raney® 2800 slurry in water, 10 g) was added in one portion
16. customthe entire apparatus was thoroughly flushed with N2
17. additiona solution of hydrazine monohydrate (8 mL) in THF/MeOH (1:1, 20 mL) was added dropwise over 1 h
18. temperatureThe mixture was heated at 60° C. for 1 h
19. temperaturecooled
20. filtrationfiltered through a pad of Celite®
21. concentrationThe filtrate was concentrated in vacuo
22. customthe residue was partitioned between Et2O/H2O
23. customthe layers were separated
24. extractionthe aqueous layer was extracted with Et2O (×3)
25. washCombined organics were washed (10% HCl, H2O, brine)
26. dry with materialdried over Na2SO4
27. filtrationfiltered
28. concentrationconcentrated in vacuo
29. customThe residue was purified by flash chromatography (EtOAc/hexanes)

ORD record

ord-3ebf3dd6c288414699a1fd1dbe54b05c

Source dataset

uspto-grants-2009_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07572820B2