Ethyl Acetate → Methyl 6-chloro-indoline-2-carboxylate

HRID 392090Notes

Reaction equation

HRID 392090 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14]C)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Mg].[Cl-].[NH4+].C(OCC)(=O)C>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([C:11]([O:13][CH3:14])=[O:12])[NH:8]2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 5462224MagnesiumHCID 7015027Ethyl 6-chloroindole-2-carboxylate

Product 1

HCID 21868710Methyl 6-chloro-indoline-2-carboxylateYield 63.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a stirred suspension-solution of ethyl 6-chloroindole-2-carboxylate (20.0 g, 89.4 mmol) in methanol (350 mL) under Ar was added magnesium turnings (21.7 g, 0.89 mol). After 10 min, the internal temperature had risen to 24° C. and effervescence was apparent. The mixture was cooled to 10-1S ° C. and was maintained for 1.5 h. After this time, the reaction mixture was allowed to warm to ambient temperature, and was stirred for 1 h. The mixture was poured onto saturated aqueous ammonium chloride solution (1 L), and ethyl acetate (300 mL) was added. After 1.5 h stirring, the layers were separated, and the aqueous layer was exacted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (200 mL), dried (magnesium sulfate) and concentrated in vacuo to give a brown oil. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] afforded the title compound (12.0 g, 63%) as an orange oil which crystallised on standing: IR νmax (film)t/cm−1 3375, 2953, 2851,1737, 1610, 1486, 1438, 1321, 1287, 1204, 1161, 1069, 1011, 948, 906, 846, 796, 794, 594 and 548; NMR δH (400 MHz; CDCl3) 3.27 (1H, dd, J 16.0, 5.0 Hz), 3.34 (1H, ddd, J 16.0, 10.5, 1.0 Hz), 3.76 (3H, s), 4.40 (1H, dd, J 10.5, 5.0 Hz), 4.47 (H, br s), 6.68 (1H, br d, J 2 Hz), 6.69 (1H, dd, J 7.5, 2.0 Hz) and 6.96 (1H, d, J 7.5 Hz); hplc [Chiralcel OD; hexane-isopropanol (90:10); 1 mL/min; 260 nm] 50% (10.04 min) and 50% (11.61 min).

Workup

  1. customhad risen to 24° C.
  2. temperatureThe mixture was cooled to 10-1S ° C
  3. temperatureand was maintained for 1.5 h
  4. additionwas added
  5. stirringAfter 1.5 h stirring
  6. customthe layers were separated
  7. washThe combined organic extracts were washed with brine (200 mL)
  8. dry with materialdried (magnesium sulfate)
  9. concentrationconcentrated in vacuo
  10. customto give a brown oil
  11. customPurification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)]

Sources & evidence

ORD record
ord-7b1e5c0eb0884689be2d728fa973cbc0
Source dataset
uspto-grants-2004_10
Patent number
US06800627B1

Reaction notes

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