1,1'-Carbonyldiimidazole → cis-Methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

HRID 1963532Notes

Reaction equation

HRID 1963532 reaction equation
[Cl-].[Mg+2].[Cl-].[C:4]([OH:10])(=[O:9])[CH2:5][C:6]([OH:8])=[O:7].[CH2:11]([K])[CH3:12].C(N1C=CN=C1)(N1[CH:20]=[CH:19]N=C1)=O.[CH3:26][C:27]([CH3:44])([CH3:43])[CH2:28][CH2:29][CH:30]1[CH2:35][CH:34]([C:36]([OH:38])=O)[CH2:33][CH2:32][N:31]1[C:39]([O:41][CH3:42])=[O:40]>C1COCC1>[CH3:44][C:27]([CH3:26])([CH3:43])[CH2:28][CH2:29][C@H:30]1[CH2:35][C@H:34]([C:6](=[O:8])[CH2:5][C:4]([O:10][CH2:11][CH3:12])=[O:9])[CH2:33][CH2:32][N:31]1[C:39]([O:41][CH3:42])=[O:40].[CH3:43][C:27]([CH3:26])([CH3:44])[CH2:28][CH2:29][C@H:30]1[CH2:35][C@@H:34]([C:36](=[O:38])[CH2:5][C:6]([O:8][CH2:19][CH3:20])=[O:7])[CH2:33][CH2:32][N:31]1[C:39]([O:41][CH3:42])=[O:40]

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 667317342-(3,3-Dimethylbutyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×HCID 178461627HCID 178461627, compound

Product 2

HCID 131730454trans-Methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 24%HCID 131730455cis-Methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

A suspension of magnesium chloride (0.852 g, 8.94 mmol) and ethyl potassium malonate (2.283 g, 13.42 mmol) in dry THF (40 mL) was stirred under nitrogen atmosphere at 50° C. for 3.5 h (flask 1). In another flask was added carbonyldiimidazole (1.740 g, 10.73 mmol) portionwise to a solution of 2-(3,3-dimethylbutyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (2.427 g, 8.94 mmol) (reference compound 42) in dry THF (40 mL) at 0° C. under nitrogen atmosphere. This solution was stirred for 1.5 h (flask 2). The contents of flask 1 was added over 10 min to flask 2 and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated and the residue was taken up in EtOAc and H2O. The aqueous phase was extracted once with EtOAc and the combined organic phase was washed with H2O, satd NaHCO3 and then dried over Na2SO4, filtered and evaporated to give a black oil. Separation using Biotage (340 g column, grad 20-30% EtOAc in heptane 7 CV) yielded trans-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (574 mg, 24%) and cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.74 g, 72%) as yellow oils. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 0.85 (s, 9H), 1.03-1.95 (m, 10H), 2.01-2.10 (m, 1H), 2.65-2.75 (m, 1H), 2.98-3.08 (m, 1H), 3.51 (s, 2H), 3.69 (s, 3H), 3.83-4.02 (m, 2H), 4.19 (q, 2H). MS m/z 342 (M+H)+. Trans-isomer: MS m/z 342 (M+H)+

Workup

  1. stirringThis solution was stirred for 1.5 h (flask 2)
  2. additionThe contents of flask 1 was added over 10 min to flask 2
  3. stirringthe resulting mixture was stirred at room temperature for 20 h
  4. concentrationThe reaction mixture was concentrated
  5. extractionThe aqueous phase was extracted once with EtOAc
  6. washthe combined organic phase was washed with H2O
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customevaporated
  10. customto give a black oil
  11. customSeparation

Sources & evidence

ORD record
ord-543166d3678644769469334573081da3
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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