Indole → (1H-Indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone

HRID 227368Notes

Reaction equation

HRID 227368 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Br)C.O1CCCC1.[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25](Cl)=[O:26]>ClCCl.[Cl-].[Cl-].[Zn+2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:25]([CH:21]2[C:22]([CH3:24])([CH3:23])[C:20]2([CH3:28])[CH3:19])=[O:26])=[CH:2]1.[CH3:19][C:20]1([CH3:28])[C:22]([CH3:24])([CH3:23])[CH:21]1[C:25]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:26]

Participants

8

Reactant 4

HCID 798IndoleHCID 8028TetrahydrofuranHCID 110410022,2,3,3-Tetramethylcyclopropane-1-carbonyl chlorideHCID 178418443HCID 178418443, compound

Product 2

HCID 24756409(1H-Indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanoneYield 42%HCID 24824340HCID 24824340, compoundYield 27%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of indole (Aldrich, 11 g, 95 mmol) in 30 mL dichloromethane at ambient temperature was added 105 mL of a 1 M solution of ethyl magnesium bromide in tetrahydrofuran (THF) (105 mmol) dropwise via syringe pump. After the addition was complete, the solution was stirred for 15 min at which time ZnCl2 (14 g, 105 mmol) was added. The mixture stirred for an additional 30 min then the product of Example 1A (95 mmol) in 50 mL dichloromethane was added via cannula. The mixture was stirred for 6 h then was quenched with 50 mL saturated aqueous NH4Cl and diluted with 50 mL dichloromethane. The layers were separated and the aqueous layer was extracted with 3×30 mL dichloromethane. The combined organics were washed with 1×20 mL H2O then were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (SiO2, 50% ethyl acetate:hexanes) to give 9.7 g of the major regioisomer 1H-indol-3-yl(2,2,3,3-tetramethylcyclopropyl)methanone (40 mmol, 42% yield) and 6.1 g of the minor regioisomer of 1-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole (25 mmol, 27% yield). MS (major and minor regioisomers) (DCI/NH3) m/z 242 (M+H)+.

Workup

  1. additionAfter the addition
  2. additionwas added
  3. stirringThe mixture was stirred for 6 h
  4. customthen was quenched with 50 mL saturated aqueous NH4Cl
  5. additiondiluted with 50 mL dichloromethane
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted with 3×30 mL dichloromethane
  8. washThe combined organics were washed with 1×20 mL H2O
  9. dry with materialthen were dried over anhydrous Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe crude material was purified via column chromatography (SiO2, 50% ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-32853a6b668b4b9eaeb4cc1108c55782
Source dataset
uspto-grants-2009_07
Patent number
US07560481B2

Reaction notes

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