Acetic Acid → 5-methoxy-2,3-dihydro-1H-indole

HRID 1014242Notes

Reaction equation

[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2

Participants

Conditions

Temperature: 10 °C

Procedure

A 4-neck 22 L round bottom flask equipped with a nitrogen inlet, mechanical stirrer and thermowell was charged with commercially available 5-methoxyindole (750 g, 5.1 mol) and acetic acid (3.75 L). The resulting solution was cooled to 10° C. by ice bath. Sodium cyanoborohydride (640 g, 10.2 mol, 2 equiv) was added portionwise to maintain the reaction temperature below 25° C. Upon the completion of addition, the reaction was stirred at room temperature for 3 hours and then water was added slowly (2.2 L). The mixture was basified to pH>12 with 50% NaOH (˜5.3 L, slow addition to avoid foaming, the temperature kept below 30° C.). The resulting mixture was extracted with dichloromethane (2×12 L). The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give 5-(methyloxy)-2,3-dihydro-1 H-indole (760 g, >90% purity), which was used for the next step without further purification. 1H NMR (CDCl3, 300 MHz) 6 6.76 (s, 1 H), 6.60 (s, 2H), 3.54 (t, 2H), 3.01 (t, 2H).

Workup

customA 4-neck 22 L round bottom flask equipped with a nitrogen inlet, mechanical stirrer
temperatureto maintain the reaction temperature below 25° C
additionUpon the completion of addition
addition˜5.3 L, slow addition
customkept below 30° C.
extractionThe resulting mixture was extracted with dichloromethane (2×12 L)
dry with materialThe combined organic layers were dried over sodium sulfate
customevaporated in vacuo

Sources & evidence

ORD record: ord-99f4c403104540419a86c6c649b27728
Source dataset: uspto-grants-2011_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07981903B2

Reaction notes

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