(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate → (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate

HRID 451705Notes

Reaction equation

HRID 451705 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[Si:10]([CH3:13])([CH3:12])[CH3:11].[Li]CCCC.CON(C)[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]>C1COCC1.CCCCCC>[F:8][C:7]1[C:2]([F:1])=[C:3]([Si:10]([CH3:12])([CH3:11])[CH3:13])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1)=[O:23]

Participants

6

Reactant 3

HCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateHCID 59201735(2,3-Difluoro-5-methylphenyl)trimethylsilaneHCID 178418339Butyllithium

Product 1

HCID 59201562(R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of (2,3-difluoro-5-methylphenyl)trimethylsilane (10 g, 0.05 mol) in anhydrous THF (100 mL) at −78° C., under nitrogen, was added dropwise a solution of 2.5 M n-BuLi in hexane (20 mL). After stirring for 1 hr at −78° C., a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (13.6 g, 0.05 mol) in anhydrous THF (60 mL) was added dropwise. After addition, the reaction mixture was allowed to warm to rt and stirred for 2 h. The mixture was quenched with saturated NH4Cl solution (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(2,3-difluoro-6-methyl-4-(trimethylsilyl)benzoyl)piperidine-1-carboxylate, which was purified by column chromatography on silica gel elating with hexane (2 g, 10%). 1H NMR δ 6.90 (m, 2H), 4.00 (m, 4H), 2.20 (s, 3H), 1.47 (s, 9H), 1.30 (m, 4H), 0.35 (s, 9H).

Workup

  1. additionAfter addition
  2. temperatureto warm to rt
  3. stirringstirred for 2 h
  4. customThe mixture was quenched with saturated NH4Cl solution (100 mL)
  5. extractionextracted with ethyl acetate (3×100 mL)
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-79c41f1f263d4ec8978044c21af97d8b
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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