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Acetic Anhydride → 2-(ethoxycarbonyl)-1-tosyl-1H-indole-5-carboxylic acid

HRID 74455
Notes
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Reaction equation

HRID 74455 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O.[CH:69]([O-:71])=[O:70].[Li+].[Cl-].[Li+].C(N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.CN(C)C=O>[CH3:2][CH2:1][O:3][C:4]([C:6]1[N:7]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:69]([OH:71])=[O:70])=[CH:10][CH:9]=2)=[O:5]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 6

HCID 7918Acetic AnhydrideHCID 81531DiisopropylethylamineHCID 433294Lithium ChlorideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 135158625-bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl esterHCID 23702287Lithium formate monohydrate

Product 1

HCID 680048532-(ethoxycarbonyl)-1-tosyl-1H-indole-5-carboxylic acid

Reagents, catalysts & solvents 3

HCID 9832798Tris(dibenzylideneacetone) dipalladiumCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of 5-bromo-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester (948.4 mg, 2.24 mmol), Tris(dibenzylideneacetone) dipalladium (0) (0.112 mmol, 103 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.225 mmol, 130 mg), lithium formate monohydrate (5.6 mmol, 394 mg), lithium chloride (286 mg, 6.75 mmol), and anhydrous N,N-dimethylformamide (DMF) (5.9 ml) was evacuated, and backfilled with argon. Then, N,N-diisopropylethyl amine (4.5 mmol, 0.78 ml) and acetic anhydride (4.5 mmol, 0.43 ml) were added to the mixture, and deaeration and argon replacement was performed again. The reaction container was placed in a reaction device preheated at 80° C. and the reaction mixture was stirred for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and an aqueous solution of 1 M hydrochloric acid, and filtered through Celite. The resulting filtrate was washed with 1 M hydrochloric acid, water, and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/3, and finally ethyl acetate/methanol=15/1) to give 1-(toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester as a yellow amorphous material (930 mg).

Workup

  1. customwas evacuated
  2. custompreheated at 80° C.
  3. filtrationan aqueous solution of 1 M hydrochloric acid, and filtered through Celite
  4. washThe resulting filtrate was washed with 1 M hydrochloric acid, water
  5. dry with materiala saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate
  6. customThe desiccant was removed by filtration
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customthe resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 to 1/3, and finally ethyl acetate/methanol=15/1)

Sources & evidence

ORD record
ord-7b4dd2cfcd1d4b6f93dd38dc3c6fd392
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08829199B2

Reaction notes

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