Bis(2-chloroethyl) ether → 4-(1H-Indol-5-yl)morpholine

HRID 2361342Notes

Reaction equation

HRID 2361342 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1

Participants

6

Reactant 3

HCID 8115Bis(2-chloroethyl) etherHCID 10340Sodium CarbonateHCID 788675-Aminoindole

Product 1

HCID 114014384-(1H-Indol-5-yl)morpholineYield 53.7%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A heterogeneous, tan solution of 1H-indol-5-amine (4.5547 g, 34.5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (6.06 mL, 51.7 mmol) and Na2CO3 (14.61 g, 138 mmol) in t-BuOH (90 mL) in a sealed pressure tube was heated to 100° C. for 2 days. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a pad of CELITE®, and the filtrate was concentrated in vacuo. Water (50 mL) was added to the residue and basified to pH ˜11 with saturated aqueous NaHCO3; this was extracted with CH2Cl2 (4×75 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product. This was triturated with Et2O to give the first crop of desired product (3.7495 g) as a tan solid. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using an ISCO 120 g column eluting with 20-50% EtOAc/hexanes to give the second crop of the desired product (1.9458 g).

Workup

  1. filtrationfiltered through a pad of CELITE®
  2. concentrationthe filtrate was concentrated in vacuo
  3. additionWater (50 mL) was added to the residue
  4. extractionthis was extracted with CH2Cl2 (4×75 mL)
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto give crude product
  10. customThis was triturated with Et2O

Sources & evidence

ORD record
ord-02654cd571f24b4e8110c54c06fda61b
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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