Sulfolane → Methyl 6-bromo-1-(sec-butyl)-3-methyl-1H-indole-4-carboxylate

HRID 1477044Notes

Reaction equation

HRID 1477044 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH:15]=O)=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O.C([BH3-])#N.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1

Participants

7

Reactant 4

HCID 31347SulfolaneHCID 521998p-Toluenesulfonic acid monohydrateHCID 5003444Sodium cyanoborohydrideHCID 78358290Methyl 6-bromo-1-(sec-butyl)-3-formyl-1H-indole-4-carboxylate

Product 1

HCID 67465536Methyl 6-bromo-1-(sec-butyl)-3-methyl-1H-indole-4-carboxylateYield 54.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of methyl 6-bromo-1-sec-butyl-3-formyl-1H-indole-4-carboxylate (15 g, 44.6 mmol) in DMF (115 mL) was added p-toluenesulfonic acid mono hydrate (1.1 g, 5.8 mmol), p-toluenesulfonyl hydrazide (10.8 g, 58 mmol) followed by sulfolane (115 mL) at RT and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, treated with sodium cyanoborohydride (11.9 g, 178.5 mmol) portion wise over a period of 5 min and stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature and stirred at the same temperature for 16 h. The reaction mixture was diluted with water and extracted with 30% EtOAc: Pet ether. The organic layer was washed with cold water (100 mL), brine (100 mL) and dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude, which was purified by column chromatography over silica gel (100-200 mesh) using 5% EtOAc: Pet ether as eluent to afford title compound methyl 6-bromo-1-sec-butyl-3-methyl-1H-indole-4-carboxylate (7.88 g, 54.6%) as pale yellow gum. 1H NMR (CDCl3, 400 MHz): δ 0.804-0.841 (t, J=7.4 Hz, 3H), 1.454-1.470 (d, J=6.4 Hz, 3H), 1.865-1.884 (m, 2H), 2.363 (s, 3H), 3.950 (s, 3H), 4.265-4.316 (m, 1H), 7.038 (s, 1H), 7.609 (d, J=1.2 Hz, 1H), 7.671 (d, J=2 Hz, 1H). MS (ES+): 324.19 [M+H] ion present.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. stirringstirred at 100° C. for 2 h
  3. temperatureThe reaction mixture was cooled to room temperature
  4. stirringstirred at the same temperature for 16 h
  5. extractionextracted with 30% EtOAc
  6. washThe organic layer was washed with cold water (100 mL), brine (100 mL)
  7. dry with materialdried over anhydrous Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customto afford crude, which
  10. customwas purified by column chromatography over silica gel (100-200 mesh)

Sources & evidence

ORD record
ord-e8d3b168ebe54f20bc13fa0909b0e318
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

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