2,2'-Bipyridine → methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate

HRID 62410

Reaction equation

HRID 62410 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][NH:8][C:9]=2[CH:10]=1.[CH:15]1(B(O)O)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][N:8]([CH:15]3[CH2:17][CH2:16]3)[C:9]=2[CH:10]=1

Participants

10

Reactant 5

HCID 14742,2'-BipyridineHCID 10340Sodium CarbonateHCID 25517Ammonium ChlorideHCID 2760897Cyclopropylboronic acidHCID 13770009methyl 6-bromo-1H-indole-4-carboxylate

Product 1

HCID 67467490methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylateYield 71.7%

Reagents, catalysts & solvents 4

HCID 8895Cupric acetateCatalystHCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
70 °C

Procedure

In a oven dried 100 ml RBF equipped, stir bar, septum and Nitrogen inlet was added methyl 6-bromo-1H-indole-4-carboxylate (0.508 g, 2.0 mmol) and 1,2-dichloroethane (7 mL). The solution was stirred for 15 min, then cyclopropylboronic acid (0.344 g, 4.00 mmol) and sodium carbonate (0.424 g, 4.00 mmol) were added. Diluted copper(II) acetate (0.363 g, 2.000 mmol) and 2,2′-bipyridine (0.312 g, 2.000 mmol) in 1,2-dichloroethane (12 mL), heated the mixture, and added the hot suspension to the reaction. The reaction was heated at 70° C. and monitored by LCMS. Stopped heating after 6 h and allowed to sit for 3 days at RT. Added to reaction saturated NH4Cl and water. Extracted with DCM (2×). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (24 g Isco silica column; gradient B: 3-25%. A: hexane. B: ethyl acetate) to give methyl 6-bromo-1-cyclopropyl-1H-indole-4-carboxylate (0.43 g, 1.433 mmol, 71.6% yield) as a yellow residue. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.01 (m, 2H) 1.06-1.12 (m, 2H) 3.52 (dt, J=7.20, 3.47 Hz, 1H) 3.90 (s, 3H) 6.85-6.91 (m, 1H) 7.57 (d, J=3.03 Hz, 1H) 7.82 (d, J=1.77 Hz, 1H) 8.04 (d, J=1.01 Hz, 1H). MS(ES) [M+H]+ 294.1.

Workup

  1. customIn a oven dried 100 ml RBF
  2. customequipped
  3. stirringThe solution was stirred for 15 min
  4. additionadded the hot suspension
  5. customto the reaction
  6. temperatureStopped heating after 6 h
  7. extractionExtracted with DCM (2×)
  8. washThe combined organics were washed with brine
  9. dry with materialdried over magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customPurification of the residue by column chromatography (24 g Isco silica column

Sources & evidence

ORD record
ord-c0ef96da48e94c549e4dab545f4231b9
Source dataset
uspto-grants-2016_09
Patent number
US09446041B2

Linked notes

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