4-Fluoroiodobenzene → Methyl 1-(4-fluorophenyl)-1h-indole-5-carboxylate

HRID 876209Notes

Reaction equation

HRID 876209 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu](I)I.C1(C)C=CC=CC=1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:16]=1

Participants

6

Reactant 3

HCID 96054-Fluoroiodobenzene2×HCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 2737635methyl 1H-indole-5-carboxylate

Product 1

HCID 59625729Methyl 1-(4-fluorophenyl)-1h-indole-5-carboxylateYield 58%

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 1140TolueneSolvent

Conditions

Temperature
85 °C

Procedure

To a 3-L 4-neck flask equipped with mechanical stirrer, N2 inlet and thermocouple was added compound 1a (124 g, 0.71 mol), toluene (0.99 L), 4-fluoro-iodobenzene (cpd 3e, 314.27 g, 1.42 mol), racemic trans-N,N′-dimethylcyclohexane-1,2-diamine (cpd 3f, 30.2 g, 0.21 mol), copper iodide (13.48 g, 0.078 mol) and tribasic-N-hydrate potassium phosphate (330.54 g, 1.56 mol). The mixture was heated to 85° C. for 12 h. A second charge of 4-fluoro-iodobenzene (47.14 g, 0.21 mol) was added and the mixture was heated to 85° C. for 4 h. The reaction mixture was filtered through a diatomaceous earth pad and was washed with CH2Cl2 (2 L). The solvent was evaporated and the residue was purified by column chromatography (2.5 Kg Biotage SiO2 column, 15 column volumes, 10% EtOAc/Heptane) to give 110 g (58%) of compound 1c. 1H NMR (Chloroform-d) δ: 8.45 (d, J=1.5 Hz, 1H), 7.92 (dd, J=8.8, 1.5 Hz, 1H), 7.41-7.50 (m, 3H), 7.34 (d, J=3.2 Hz, 1H), 7.17-7.29 (m, 1H), 6.77 (d, J=3.4 Hz, 1H), 3.94 (s, 3H).

Workup

  1. customTo a 3-L 4-neck flask equipped with mechanical stirrer, N2 inlet
  2. additionwas added
  3. temperaturethe mixture was heated to 85° C. for 4 h
  4. filtrationThe reaction mixture was filtered through a diatomaceous earth pad
  5. washwas washed with CH2Cl2 (2 L)
  6. customThe solvent was evaporated
  7. customthe residue was purified by column chromatography (2.5 Kg Biotage SiO2 column, 15 column volumes, 10% EtOAc/Heptane)

Sources & evidence

ORD record
ord-fe1a4ae443b44d938ad3a9723acb037e
Source dataset
uspto-grants-2015_03
Patent number
US08987247B2

Reaction notes

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