Toluene → 6-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehyde

HRID 338302Notes

Reaction equation

HRID 338302 reaction equation
CC1(C)COB([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)OC1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[Cl:30])[NH:26][CH:25]=[C:24]2[CH:31]=[O:32].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:30][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([CH:31]=[O:32])=[CH:25][NH:26]2)=[CH:22][C:21]=1[C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:17][CH:18]=1

Participants

7

Reactant 4

HCID 1140TolueneHCID 11430Potassium CarbonateHCID 866985665-bromo-6-chloro-1H-indole-3-carbaldehydeHCID 866986443-(4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)propan-1-ol2×

Product 1

HCID 866986486-chloro-5-[4-(3-hydroxypropoxy)phenyl]-1H-indole-3-carbaldehydeYield 44.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolvent2×

Conditions

Temperature
100 °C

Procedure

To a solution of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (4.9 g, 18.6 mmol) in ethanol (25 ml) was added 5-bromo-6-chloro-1H-indole-3-carbaldehyde (4.0 g, 15 mmol) followed by toluene (50 ml) and 2N aq. potassium carbonate (26.3 ml, 52.6 mmol). Nitrogen was bubbled though the solution for 15 min, then Pd(dppf)Cl2 (0.46 g, 0.62 mol) was added and reaction heated to 100° C. An additional portion of 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]propan-1-ol (1.0 g) in ethanol (4 ml) was added and heating continued for 30 min. The reaction was allowed to cool to room temperature and stirred for 3 days. The reaction was partitioned between water and EtOAc and stirred. The layers were separated and the organic layers were washed with water which resulted in a thick emulsion. The emulsion was filtered through celite to attempt to break the emulsion which had limited effect. Upon standing, emulsion was reduced. Layers were separated and organic washed with brine, dried over sodium sulfate, filtered and stripped. Residue was mostly dissolved in MeOH, filtered to remove solids then adsorbed onto silica gel then purified by silica gel chromatography (30-100% EtOAc/Heptane). The second peak was isolated to afford the title compound (2.2 g, 43%) as a yellow solid that was taken on to the next reaction without further purification.

Workup

  1. customNitrogen was bubbled though the solution for 15 min
  2. customreaction
  3. temperatureheating
  4. temperatureto cool to room temperature
  5. customThe reaction was partitioned between water and EtOAc
  6. stirringstirred
  7. customThe layers were separated
  8. washthe organic layers were washed with water which
  9. customresulted in a thick emulsion
  10. filtrationThe emulsion was filtered through celite
  11. customLayers were separated
  12. washorganic washed with brine
  13. dry with materialdried over sodium sulfate
  14. filtrationfiltered
  15. dissolutionResidue was mostly dissolved in MeOH
  16. filtrationfiltered
  17. customto remove solids
  18. customthen purified by silica gel chromatography (30-100% EtOAc/Heptane)
  19. customThe second peak was isolated

Sources & evidence

ORD record
ord-3a6432da3e4e4a6d9fad6c707e39cc8d
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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