1,4-Dioxane → methyl 6-(4-fluoro-3-formylphenyl)-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate

HRID 42440Notes

Reaction equation

HRID 42440 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH:29]=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O.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(Cl)Cl.CCOC(C)=O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:22][C:21]=1[CH:29]=[O:30]

Participants

8

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 2778651(4-Fluoro-3-formylphenyl)boronic acidHCID 67464634methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate

Product 1

HCID 86677352methyl 6-(4-fluoro-3-formylphenyl)-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylateYield 98.3%

Reagents, catalysts & solvents 3

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a glass pressure vessel was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), 4-fluoro-3-formylbenzeneboronic acid (375 mg, 2.233 mmol), Potassium phosphate (1.1 g, 5.18 mmol), dioxane (12 mL) and water (3 mL). The reaction was purged with N2 and charged with PdCl2(dppf)-CH2Cl2 adduct (120 mg, 0.147 mmol). The reaction was capped and stirred at 110° C. for 4 hr. LCMS showed that the reaction was complete. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 0 to 50% EtOAc in hexanes) gave the product methyl 6-(4-fluoro-3-formylphenyl)-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (560 mg, 1.585 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.30 (s, 1H), 8.24-8.13 (m, 2H), 8.10 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.57-7.46 (m, 2H), 4.98 (quip, J=6.6 Hz, 1H), 3.91 (s, 3H), 2.31 (s, 3H), 1.46 (d, J=6.6 Hz, 6H). MS (ES)+m/e 354.2 [M+H]+.

Workup

  1. customThe reaction was purged with N2
  2. customThe reaction was capped
  3. extractionextracted with EtOAc
  4. washwashed with brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated under vacuum
  8. customPurification by silica gel chromatography (Analogix

Sources & evidence

ORD record
ord-73474064a1d54622bedc02bb6d57e551
Source dataset
uspto-grants-2013_09
Patent number
US08536179B2

Reaction notes

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