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

HRID 1963352Notes

Reaction equation

HRID 1963352 reaction equation
[C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([K])[CH3:9].[Mg+2].[Cl-].[Cl-].[CH:14]1([CH2:20][CH:21]2[CH2:26][CH:25]([C:27]([OH:29])=O)[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N1C=CN=C1)(N1[CH:40]=[CH:39]N=C1)=O>C1COCC1>[CH:14]1([CH2:20][C@H:21]2[CH2:26][C@H:25]([C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH:14]1([CH2:20][C@H:21]2[CH2:26][C@@H:25]([C:27](=[O:29])[CH2:2][C:3]([O:5][CH2:39][CH3:40])=[O:4])[CH2:24][CH2:23][N:22]2[C:30]([O:32][CH3:33])=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1

Participants

7

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 667322852-(Cyclohexylmethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid2×HCID 178461627HCID 178461627, compound

Product 2

HCID 131730376trans-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 16%HCID 131730377cis-Methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylateYield 53%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

Ethyl potassium malonate (1.75 g, 10.3 mmol) and MgCl2 (0.665 g, 6.88 mmol) were added to dry THF (50 mL). The reaction flask was stirred vigorously 4 h at 50° C. (flask 1). 2-(Cyclohexylmethyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.95 g, 6.88 mmol) (Reference Compound 8) and carbonyldiimidazole (1.34 g, 8.26 mmol) were added to dry THF (50 mL) at 5° C. (flask 2). The contents of flask 2 was added to flask 1 at room temperature. The reaction mixture was evaporated to remove most of the THF. The crude was partitioned between water and diethyl ether. The organic phase was isolated, dried with MgSO4, filtered through Celite® and the solvent was evaporated. The residue was purified by automated column chromatography using the Biotage equipment. Gradient eluation using ethylacetate-heptane, started 15-85 and ended 40-60 which gave trans-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.38 g, 16%) and cis-methyl 2-(cyclohexylmethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.28 g, 53%). Trans-isomer: 1H NMR (600 MHz, cdcl3) δ 0.88 (d, 2H), 0.99-1.32 (m, 8H), 1.38-1.56 (m, 2H), 1.68 (dd, 8H), 2.80 (t, 2H), 3.45 (s, 2H), 3.66 (s, 3H), 3.93-4.21 (m, 3H), 4.47 (d, 1H). Cis-isomer 1H NMR (600 MHz, cdcl3) δ 0.72-0.95 (m, 2H), 1.04-1.31 (m, 8H), 1.38-1.49 (m, 1H), 1.53-1.69 (m, 6H), 1.70-1.92 (m, 3H), 2.02 (dt, 1H), 2.61-2.71 (m, 1H), 2.95-3.07 (m, 1H), 3.48 (s, 2H), 3.66 (s, 3H), 3.85 (dd, 1H), 4.09-4.21 (m, 3H).

Workup

  1. additionThe contents of flask 2 was added to flask 1 at room temperature
  2. customThe reaction mixture was evaporated
  3. customto remove most of the THF
  4. customThe crude was partitioned between water and diethyl ether
  5. customThe organic phase was isolated
  6. dry with materialdried with MgSO4
  7. filtrationfiltered through Celite®
  8. customthe solvent was evaporated
  9. customThe residue was purified by automated column chromatography

Sources & evidence

ORD record
ord-9417db6c4a934396bdde3db635ce078f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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