1-Bromo-3-chloro-5-fluorobenzene → (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate

HRID 451994Notes

Reaction equation

HRID 451994 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Mg].CON(C)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]

Participants

5

Reactant 3

HCID 27362231-Bromo-3-chloro-5-fluorobenzeneHCID 5462224MagnesiumHCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate

Product 1

HCID 58017408(R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylateYield 98%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 1-bromo-3-chloro-5-fluoro-benzene (31.5 g, 0.15 mol) in anhydrous THF (120 mL) was added dropwise to the Mg (5.4 g, 0.22 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr until most of the magnesium was consumed. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (20.4 g, 0.075 mol) in anhydrous THF (200 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (25 g, 98%), which was used in the next step without further purification.

Workup

  1. customwas consumed
  2. additionAfter addition
  3. customThe mixture was quenched with saturated NH4Cl solution (300 mL)
  4. extractionextracted with EtOAc (3×200 mL)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-160f9ff66c204ff6a59abdb3817ee3cd
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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