Dimethylformamide → methyl 6-bromo-1H-indole-4-carboxylate

HRID 1477035Notes

Reaction equation

HRID 1477035 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([CH3:11])=[C:6]([CH:10]=1)C(O)=O.CN([CH:18]([O:21]C)[O:19][CH3:20])C.[CH3:23]N(C=O)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:10]=[C:6]([C:18]([O:19][CH3:20])=[O:21])[C:5]2[CH:11]=[CH:23][NH:12][C:4]=2[CH:3]=1

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 78373Dimethylformamide dimethyl acetalHCID 137700085-Bromo-2-methyl-3-nitrobenzoic acid

Product 1

HCID 13770009methyl 6-bromo-1H-indole-4-carboxylateYield 59%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 176Acetic AcidSolvent

Conditions

Temperature
115 °C

Procedure

To a stirred solution of 5-bromo-2-methyl-3-nitro-benzoic acid (140 g, 538.4 mmol) in DMF (550 ml) was added DMF-DMA (599 mL, 4846 mmol) at room temperature. The reaction mixture was stirred at 115° C. for 18 h. The reaction mixture was then concentrated in vacuo. The residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL) and added to a suspension of iron (329.2 g, 5902 mmol) in acetic acid (1.4 L) at 50° C. After completion of addition, the reaction mixture was stirred at 80-90° C. for 4 h. The reaction mixture was then filtered through a Celite pad. The filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3×700 ml). The combined organic layers were washed with sat NaHCO3, brine, and dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by silica gel chromatography (eluent: 10% ethyl acetate in pet ether) and afforded the title compound as a solid (80 g, 59%). 1H NMR (DMSO-d6, 400 MHz) δ: 3.980 (s, 3H), 7.168 (d, J=3.2 Hz, 1H), 7.334 (d, J=3.2 Hz, 1H), 7.734 (s, 1H), 8.017 (s, 1H), 8.384 (brs, 1H); LCMS (ES−) m/z=251.9 (M−H).

Workup

  1. concentrationThe reaction mixture was then concentrated in vacuo
  2. dissolutionThe residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL)
  3. additionAfter completion of addition
  4. stirringthe reaction mixture was stirred at 80-90° C. for 4 h
  5. filtrationThe reaction mixture was then filtered through a Celite pad
  6. additionThe filtrate was poured onto ice water (1 L)
  7. extractionextracted with diethyl ether (3×700 ml)
  8. washThe combined organic layers were washed with sat NaHCO3, brine
  9. dry with materialdried over anhydrous Na2SO4
  10. filtrationfiltered
  11. customevaporated under vacuum
  12. customThe crude product was purified by silica gel chromatography (eluent: 10% ethyl acetate in pet ether)

Sources & evidence

ORD record
ord-4b9d3f6f113e411a84c9c3243c574e7b
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

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