Tert-butyl 4-iodopiperidine-1-carboxylate → Tert-butyl 4-(1-benzofuran-4-yl)piperidine-1-carboxylate

HRID 1487925Notes

Reaction equation

HRID 1487925 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:33]=[CH:32][CH:28]2[CH:29]=[CH:30][O:31][CH:27]2[CH:26]=1.Br[C:35]1[CH:40]2[CH:41]=[CH:42][O:43][CH:39]2[CH:38]=[CH:37][CH:36]=1>CC(N(C)C)=O.[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]>[O:31]1[C:27]2[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][C:28]=2[CH:29]=[CH:30]1.[O:43]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([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)[C:40]=2[CH:41]=[CH:42]1

Participants

10

Reactant 4

HCID 10892302Tert-butyl 4-iodopiperidine-1-carboxylateHCID 86760839Chlorotrimethylsilane 1,2-dibromoethaneHCID 900211296-Bromo-3a,7a-dihydrobenzofuran2×HCID 900211904-Bromo-3a,7a-dihydrobenzofuran2×

Product 2

HCID 90022159Tert-butyl 4-(1-benzofuran-4-yl)piperidine-1-carboxylateYield 7%HCID 90066663Tert-butyl 4-(benzofuran-6-yl)piperidine-1-carboxylateYield 6%

Reagents, catalysts & solvents 4

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 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 (1.13 g, 17.3 mmol) in DMA (5 mL). A 7:5 v/v mixture of TMSCl/1,2-dibromoethane (0.5 mL) was added to the reaction flask drop-wise to maintain the temperature below 65° C., then the mixture was stirred for an additional 10 min. To this mixture was added a solution of tert-butyl 4-iodopiperidine-1-carboxylate (5.40 g, 17.4 mmol) in DMA (40 mL) drop-wise with stirring and the resulting mixture was stirred at room temperature for 1 hour. The above mixture was filtered, and added to a mixture of 6-bromo-3a,7a-dihydrobenzofuran (compound 63.2) and 4-bromo-3a,7a-dihydrobenzofuran (compound 63.3) (2.83 g, 14.2 mmol), and CuI (274 mg, 1.44 mmol), Pd(dppf)Cl2 (1.18 g, 1.6 mmol) in DMA (30 mL). The resulting mixture was stirred overnight at 85° C., then cooled to room temperature. The solids were removed by filtration and the filtrate was diluted with ethyl acetate (200 mL) and washed with brine (3×80 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/30˜1/20) as the eluent to yield tert-butyl 4-(1-benzofuran-6-yl)piperidine-1-carboxylate (compound 63.4) as a colorless oil (267 mg, 6%) and tert-butyl 4-(1-benzofuran-4-yl)piperidine-1-carboxylate (compound 63.5) as an off-white solid (320 mg, 7%).

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 to the reaction flask drop-wise
  4. temperatureto maintain the temperature below 65° C.
  5. stirringwith stirring
  6. stirringthe resulting mixture was stirred at room temperature for 1 hour
  7. filtrationThe above mixture was filtered
  8. stirringThe resulting mixture was stirred overnight at 85° C.
  9. customThe solids were removed by filtration
  10. additionthe filtrate was diluted with ethyl acetate (200 mL)
  11. washwashed with brine (3×80 mL)
  12. dry with materialdried (Na2SO4)
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/30˜1/20) as the eluent

Sources & evidence

ORD record
ord-f75a40f866254df58e4215b5cc980257
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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