Ethanol → Methyl 6-chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylate

HRID 1054857Notes

Reaction equation

HRID 1054857 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([O:14][CH3:15])=[O:13].CC1(C)COB([C:23]2[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=2)OC1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:23]1[CH:32]=[CH:31][C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=1

Participants

8

Reactant 4

HCID 702EthanolHCID 11430Potassium CarbonateHCID 86698569methyl 5-bromo-6-chloro-1H-indole-3-carboxylateHCID 866986342-[4-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy]ethanol

Product 1

HCID 86698844Methyl 6-chloro-5-(4-(2-hydroxyethoxy)phenyl)-1H-indole-3-carboxylateYield 98.8%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (5.2 g, 18.0 mmol), 2-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenoxy)ethanol (5.7 g, 22.8 mmol), PdCl2(dppf) (0.54 g, 0.72 mmol), 2 M aqueous solution of potassium carbonate (27 ml, 54.0 mmol), ethanol (30 ml), and toluene (90 ml) was stirred in a closed bottle at 80° C. for 2 hours and at 90° C. for 2 more hours. The reaction mixture was cooled to room temperature, ethyl acetate (50 ml) was added, and the mixture was filtered through a pad of Celite. The organic phase of the mother liquor was separated. Filter cake was washed with 10% of methanol in THF and this wash was combined with the first organic extract. The combined organic solution was dried over anhydrous magnesium sulfate and loaded on silica gel. Chromatography on a silica gel column, eluting with a gradient from 40% to 90% of ethyl acetate in heptanes to give the title compound (6.15 g, 98%). MS (ES+) 346.0 (M+1)+. 1H NMR (CDCl3): δ 8.74 (br. s, 1H), 8.13 (s, 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 4.18 (t, 2H), 4.02 (t, 2H), 3.92 (s, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationthe mixture was filtered through a pad of Celite
  3. customThe organic phase of the mother liquor was separated
  4. filtrationFilter cake
  5. washwas washed with 10% of methanol in THF
  6. dry with materialThe combined organic solution was dried over anhydrous magnesium sulfate
  7. washChromatography on a silica gel column, eluting with a gradient from 40% to 90% of ethyl acetate in heptanes

Sources & evidence

ORD record
ord-c81d92d034c9496e831fc0bc2ae40fd0
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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