Diisopropylamine → Tert-butyl 4-cyano-4-(cyclopropylmethyl)piperidine-1-carboxylate

HRID 551139Notes

Reaction equation

HRID 551139 reaction equation
[CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[C:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14].C1(CBr)CC1>C1COCC1>[C:13]([C:15]1([CH2:1][CH:2]2[CH2:4][CH2:3]2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)#[N:14]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 81503BromomethylcyclopropaneHCID 1514443Tert-butyl 4-cyanopiperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 57425738Tert-butyl 4-cyano-4-(cyclopropylmethyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

n-Butyllithium in hexanes (1.6M, 11.2 mL, 17.9 mmol) was added dropwise to diisopropylamine (2.5 mL, 17.8 mmol) in THF (20 mL) cooled in an ice bath. After stirring for 0.5 h, the solution was cooled in a dry-ice bath and a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (I-1) (2.50 g, 11.9 mmol) in THF (20 mL) was added dropwise. The solution was stirred in a dry-ice bath for 1 h then cyclopropylmethyl bromide (1.27 mL, 13.1 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h then quenched with water. The mixture was extracted with DCM (3×). The combined organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. Biotage chromatography (5-10% ethyl acetate-hexanes) afforded tert-butyl 4-cyano-4-cyclopropylmethylpiperidine-1-carboxylate (I-2) as a colourless oil. 1H NMR (500 MHz, CDCl3): δ 4.12 (br s, 2H), 3.05 (br s, 2H), 2.02 (m, 2H), 1.52 (d, J=7.0, 2H), 1.46 (s, 9H), 0.89 (m, 1H), 0.58 (m, 2H), 0.19 (m, 2H).

Workup

  1. temperaturecooled in an ice bath
  2. temperaturethe solution was cooled in a dry-ice bath
  3. stirringThe solution was stirred in a dry-ice bath for 1 h
  4. customthen quenched with water
  5. extractionThe mixture was extracted with DCM (3×)
  6. washThe combined organic phase was washed with brine
  7. dry with materialdried (MgSO4)
  8. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-3e6a673907164d379c69c895f7979fd1
Source dataset
uspto-grants-2011_05
Patent number
US07947714B2

Reaction notes

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