Lithium Hexamethyldisilazide → 4-(1-Cyclopropyl-4-methylpiperidin-4-yl)aniline

HRID 1050569Notes

Reaction equation

HRID 1050569 reaction equation
C1([N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(N)=O)=NC=C(N5CCC[C@@H](NC(N(C)C)=O)[C@H]5C)N=4)=[CH:14][CH:13]=3)([CH3:11])[CH2:7][CH2:6]2)CCC1.C1(P([C:54]2C=CC=C[C:55]=2[C:60]2C=CC=CC=2)C2CCCCC2)CCCCC1.[Li+].C[Si]([N-][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]>[CH:60]1([N:5]2[CH2:6][CH2:7][C:8]([C:12]3[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=3)([CH3:11])[CH2:9][CH2:10]2)[CH2:55][CH2:54]1

Participants

6

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 118114803US9656988, Example 246

Product 1

HCID 1181147254-(1-Cyclopropyl-4-methylpiperidin-4-yl)anilineYield 402%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a suspended of 4-(4-bromophenyl)-1-cyclopropyl-4-methylpiperidine (341) (16.0 g, 54.5 mmol), (dicyclohexylphosphino)biphenyl (1.9 g, 5.4 mmol) and Pd2(dba)3 (2.5 g, 27.2 mmol) in anhydrous THF (100 mL) was added LiHMDS (1M, 109 mL, 109 mmol). The resulting mixture was purged with N2 and then stirred at 60° C. for overnight under N2 atmosphere. After cooled down to RT, the mixture was diluted with water (100 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried, concentrated and subjected to silica flash column chromatography using 0 to 50% EtOAc in PE to give 4-(1-cyclopropyl-4-methylpiperidin-4-yl)aniline (342) (5 g, 40%) as a white solid. Proton NMR (CDCl3): δ 7.16 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.6 Hz), 3.58 (2H, s), 2.82-2.65 (2H, m), 2.64-2.49 (2H, m), 2.14-2.04 (2H, m), 1.77-1.65 (2H, m), 1.21 (3H, s), 0.96-0.82 (1H, m), 0.56-0.28 (4H, m) ppm.

Workup

  1. customThe resulting mixture was purged with N2
  2. temperatureAfter cooled down to RT
  3. additionthe mixture was diluted with water (100 mL)
  4. extractionextracted with DCM (50 mL×3)
  5. washThe combined organic layers were washed with brine
  6. customdried
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-9375a80a0897417e941d7c02d34855a2
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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