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Chlorotrimethylsilane → Tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylate

HRID 1057029
Notes
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Reaction equation

HRID 1057029 reaction equation
C[Si](Cl)(C)C.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](I)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:24][C:25]1[CH:30]=[C:29](I)[CH:28]=[C:27]([Cl:32])[N:26]=1>CN(C)C(=O)C.CCOC(C)=O.O.[Zn].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].[Cu]I>[Cl:24][C:25]1[CH:30]=[C:29]([CH:20]2[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]2)[CH:28]=[C:27]([Cl:32])[N:26]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

11

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 10892302Tert-butyl 4-iodopiperidine-1-carboxylateHCID 117373932,6-Dichloro-4-iodopyridine

Product 1

HCID 90015259Tert-butyl 4-(2,6-dichloropyridin-4-yl)piperidine-1-carboxylateYield 62%

Reagents, catalysts & solvents 6

HCID 23994
Zinc
Catalyst
HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst
HCID 178477754HCID 178477754, compoundCatalyst
HCID 962WaterSolvent
HCID 8857Ethyl AcetateSolvent
HCID 31374DimethylacetamideSolvent3×

Procedure

Under a nitrogen atmosphere, zinc dust (4.06 g, 62.1 mmol) was suspended in N,N-dimethylacetamide (5 mL) and a mixture of trimethylsilylchloride (0.946 mL, 7.30 mmol) and 1,2-dibromoethane (0.636 mL, 7.30 mmol) was added cautiously over 10 min. After stirring for a further 15 min, a solution of N-(tert-butoxycarbonyl)-4-iodopiperidine (16.74 g, 51.11 mmol) in N,N-dimethylacetamide (20 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with a small amount of N,N-dimethylacetamide. The resulting yellow solution was injected into a separately prepared, nitrogen flushed suspension of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.35 g, 1.83 mmol), copper(I) iodide (695 mg, 3.65 mmol) and 2,6-dichloro-4-iodopyridine (10.0 g, 36.5 mmol) in N,N-dimethylacetamide (30 mL) and this mixture was stirred at 80° C. for 16.5 hr. After cooling to rt, the mixture was diluted with EtOAc and water and partitioned. Filtration through Celite was necessary to break the emulsion, following which, the organics were washed with water and then dried over MgSO4. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) to afford tert-butyl 4-(2,6-dichloro-4-pyridyl)piperidine-1-carboxylate as a white solid (7.49 g, 62%); 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 2H), 4.19 (m, 2H), 2.78 (m, 2H), 2.71 (m, 1H), 1.81 (m, 2H), 1.65 (m, 2H), 1.48 (s, 9H).

Workup

  1. additionwas added cautiously over 10 min
  2. stirringstirring
  3. waitwas continued for an additional 30 min
  4. filtrationIn the open atmosphere, this mixture was filtered through Celite as quickly as possible,
  5. washrinsing with a small amount of N,N-dimethylacetamide
  6. customa separately prepared
  7. customnitrogen flushed
  8. stirringthis mixture was stirred at 80° C. for 16.5 hr
  9. custompartitioned
  10. filtrationFiltration through Celite
  11. washthe organics were washed with water
  12. dry with materialdried over MgSO4
  13. customthe resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc)

Sources & evidence

ORD record
ord-de704dfcaa2a48b186268d8239c22b2c
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09399636B2

Reaction notes

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