Nitroethane → methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate

HRID 1477066Notes

Reaction equation

HRID 1477066 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.[N+](CC)([O-])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[C:6]([F:19])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1

Participants

4

Reactant 3

HCID 6587NitroethaneHCID 2724933SelectfluorHCID 67466539methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate

Product 1

HCID 67466589methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylateYield 20.7%

Procedure

To a 20 ml vial was added methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (50.0 mg, 0.169 mmol), (selectfluor) 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (78 mg, 0.219 mmol) followed with a magnetic stir bar and nitroethane (2 ml). The vial was capped and the reaction stirred at room temperature. Reaction progress was monitored by LCMS. After reaction completion the reaction solvent was removed in-vacuo. The residue was dissolved with DCM(1.4 ml). The DCM solution was charged onto an analogix Si35 SF10-8 gram column. The compound was eluted with EtOAc/Hexanes, 5-15%, 20 min. The desired product and side MW629 co-eluted. The mixture was dissolved with DMSO (1 ml) and purified by reverse phase HPLC using a Gemini 5μ 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient. The desired product eluted at 6.8 minutes and the side product MW 629 at 9.5 minutes. The desired fractions were concentrated to a residue. LCMS and NMR support the desired structure and analytical HPLC showed 100% purity. The product, methyl 6-bromo-3-fluoro-1-isopropyl-1H-indole-4-carboxylate (11 mg, 0.035 mmol, 20.53% yield), was obtained as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (t, J=1.77 Hz, 1H), 7.78 (d, J=1.77 Hz, 1H), 7.47 (d, J=2.53 Hz, 1H), 4.76-4.84 (m, J=1.64, 6.65, 6.65, 13.36 Hz, 1H), 3.96 (s, 3H), 1.50 (d, 6H).

Workup

  1. customfollowed with a magnetic stir bar
  2. customThe vial was capped
  3. customReaction progress
  4. customAfter reaction completion the reaction solvent
  5. customwas removed in-vacuo
  6. dissolutionThe residue was dissolved with DCM(1.4 ml)
  7. additionThe DCM solution was charged onto an analogix Si35 SF10-8 gram column
  8. washThe compound was eluted with EtOAc/Hexanes, 5-15%, 20 min
  9. dissolutionThe mixture was dissolved with DMSO (1 ml)
  10. custompurified by reverse phase HPLC
  11. custom5μ 30×100 mm column, neutral acetonitrile/0.1% formic acid in water, 50-80%, 7 min gradient
  12. washThe desired product eluted at 6.8 minutes
  13. concentrationThe desired fractions were concentrated to a residue

Sources & evidence

ORD record
ord-922af7f8758245299fcff1d18ae193c1
Source dataset
uspto-grants-2016_08
Patent number
US09402836B2

Reaction notes

Loading…