5-bromo-1H-indazole → tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylate

HRID 1487921Notes

Reaction equation

HRID 1487921 reaction equation
C[Si](Cl)(C)C.BrCCBr.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[CH:28]2>CC(N(C)C)=O.C(OCC)(=O)C.[Zn].[Cu]I.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]>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1

Participants

9

Reactant 3

HCID 7619295-bromo-1H-indazoleHCID 10892302Tert-butyl 4-iodopiperidine-1-carboxylateHCID 86760839Chlorotrimethylsilane 1,2-dibromoethane

Product 1

HCID 49760224tert-butyl 4-(1H-indazol-5-yl)piperidine-1-carboxylateYield 13.1%

Reagents, catalysts & solvents 5

HCID 23994ZincCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent3×

Procedure

Into a 50-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a suspension of Zn (990 mg, 15.1 mmol) in DMA (1 mL) A 7:5 v/v mixture of TMSCl/1,2-dibromoethane (0.12 mL) was added drop-wise at a rate to maintain the temperature below 65° C., then the mixture was stirred for an additional 10 min. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (3.17 g, 10.2 mmol) in DMA (2 mL) was added drop-wise and stirred at 40-45° C. for 30 min. The resulting mixture was added to a mixture of 5-bromo-1H-indazole (1.00 g, 5.08 mmol), CuI (80 mg, 0.42 mmol) and Pd(dppf)Cl2 (260 mg, 0.36 mmol) in DMA (1 mL) in a 50-mL round-bottom flask under a nitrogen atmosphere. The resulting mixture was stirred overnight at 85° C., then cooled and diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as the eluent to yield the title compound as a yellow solid (200 mg, 12%).

Workup

  1. customInto a 50-mL three neck round-bottom flask, which was purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. additionwas added drop-wise at a rate
  4. temperatureto maintain the temperature below 65° C.
  5. stirringstirred at 40-45° C. for 30 min
  6. stirringThe resulting mixture was stirred overnight at 85° C.
  7. temperaturecooled
  8. washwashed with brine (3×20 mL)
  9. dry with materialdried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) as the eluent

Sources & evidence

ORD record
ord-eeaa12eec5d24c3fa1ef385aad1a725f
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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