Lithium Hexamethyldisilazide → Tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate

HRID 1050546Notes

Reaction equation

HRID 1050546 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:27][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1>[NH2:27][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 2733832Lithium HexamethyldisilazideHCID 118115382Tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate

Product 1

HCID 118115227Tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylateYield 36%

Reagents, catalysts & solvents 3

HCID 27342162-(Dicyclohexylphosphino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
65 °C

Procedure

A sealed tube was charged with tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (2.6 g, 7.37 mmol), (dicyclohexylphosphino)biphenyl (65 mg, 0.18 mmol), Pd2(dba)3 (68 mg, 0.074 mmol) and LiHMDS (1M, 14.7 mL, 14.7 mmol) in anhydrous THF (15 mL). The resulting mixture was purged with N2 stream and stirred in 65° C. bath for overnight. After being cooled to RT, the mixture was diluted with water (10 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine, dried, concentrated in vacuo, and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to afford tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (750 mg, 36%) as a white solid. Proton NMR (CDCl3): δ 7.13 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 3.67-3.57 (2H, m), 3.54-3.44 (2H, m), 3.43-3.33 (2H, m), 2.03 (2H, s), 1.67-1.61 (2H, m), 1.47 (9H, s), 1.22 (3H, s) ppm.

Workup

  1. customThe resulting mixture was purged with N2 stream
  2. temperatureAfter being cooled to RT
  3. additionthe mixture was diluted with water (10 mL)
  4. extractionextracted with DCM (5 mL×3)
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c7d7a73e0d5e454e8ca5ec77d5fcbb19
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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