Benzenesulfonyl chloride → 2-chloro-5-methoxy-1H-indole

HRID 2292758Notes

Reaction equation

HRID 2292758 reaction equation
COC(=O)C[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[Cl:16].C([Li])(CC)C.C1CCCCC1.CN(CN1C2C(=CC(OC)=CC=2)C=C1)C.C1(S(Cl)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:6]1[NH:7][C:8]2[C:13]([CH:5]=1)=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2

Participants

6

Reactant 4

HCID 7369Benzenesulfonyl chlorideHCID 10608272HCID 10608272, compoundHCID 10824783HCID 10824783, compoundHCID 178418403HCID 178418403, compound

Product 1

HCID 105835622-chloro-5-methoxy-1H-indoleYield 29%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

2-Chloro-5-methoxy-1H-indole-3-acetic acid methyl ester. Cooling with a dry ice-ethanol bath, 20 mL (0.026 mol) of 1.3M sec-butyl lithium/cyclohexane was added to 5.1 g (0.025 mol) of 1-dimethylaminomethyl-5-methoxy-1H-indole in 100 mL of THF keeping the temperature below -50° C. The cooling bath was removed and the temperature allowed to reach 0° C. and the bath then replaced. At -60° C., 3.32 mL (0.026 mol) of benzenesulfonyl chloride in 10 mL of THF was added, stirred 0.3 hours, the bath removed, and the temperature allowed to reach 20° C. over 1 hour. To this mixture was added 100 mL of 1N HCl and 50 mL of EtOAc and the mixture stirred for 20 hours. After making basic with 5N NaOH, the EtOAc layer was separated, washed with water, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica eluting with toluene to give 1.37 g (29% yield) of crude 2-chloro-5-methoxy-1H-indole. To this material (7.55 mmol) in 30 mL of THF was added 4.7 mL (7.55 mmol) of 1.6M n-butyl lithium/hexane keeping the temperature below 10° C. with an ethanol-ice bath. After 0.25 h, 7.55 mL (7.55 mmol) of 1M ZnCl2 /ether was added, stirred 2 hours, concentrated at reduced pressure, and 40 mL of toluene added followed by 0.72 mL (7.55 mmol) of methyl 2-bromoacetate. The mixture was stirred for 16 hours, warmed at 76° C. for 4 h, cooled, and 50 mL of 1N HCl and 40 mL of EtOAc added. After 0.5 hour, the organic layer was separated, dried (Na2SO4), and concentrated at reduced pressure. The residue was chromatographed on silica and eluted with a solvent gradient (toluene→20% EtOAc/toluene) to give 0.79 g (41% yield) of 2-chloro-5-methoxy-1H-indole-3-acetic acid methyl ester, as an oil.

Workup

  1. temperatureCooling with a dry ice-ethanol bath
  2. customThe cooling bath was removed
  3. customto reach 0° C.
  4. customthe bath removed
  5. waitto reach 20° C. over 1 hour
  6. additionTo this mixture was added 100 mL of 1N HCl and 50 mL of EtOAc
  7. stirringthe mixture stirred for 20 hours
  8. customthe EtOAc layer was separated
  9. washwashed with water
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated at reduced pressure
  12. customThe residue was chromatographed on silica eluting with toluene

Sources & evidence

ORD record
ord-b13d144a928045548b7eb190af8785fd
Source dataset
uspto-grants-1997_11
Patent number
US05684034

Reaction notes

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