1,1'-Carbonyldiimidazole → HCID 131730437, compound

HRID 1963492Notes

Reaction equation

HRID 1963492 reaction equation
[Cl-].[Mg+2].[Cl-].[C:4]([OH:10])(=[O:9])[CH2:5][C:6]([OH:8])=O.[CH2:11]([K])[CH3:12].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:26]1([CH:32]2[CH2:37][CH:36](C(O)=O)[CH2:35][CH2:34][N:33]2[C:41]([O:43][CH3:44])=[O:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1>[CH:26]1([C@H:32]2[CH2:37][C@H:36]([C:6](=[O:8])[CH2:5][C:4]([O:10][CH2:11][CH3:12])=[O:9])[CH2:35][CH2:34][N:33]2[C:41]([O:43][CH3:44])=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 5360315Magnesium ChlorideHCID 66731984HCID 66731984, compound2×HCID 178461627HCID 178461627, compound

Product 1

HCID 131730437HCID 131730437, compoundYield 8.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
50 °C

Procedure

A suspension of magnesium chloride (2.085 g, 21.89 mmol) and ethyl potassium malonate (3.73 g, 21.89 mmol) in dry THF (80 mL) was stirred under nitrogen atmosphere at 50° C. for 2.5 h (flask 1). In another flask di(1H-imidazol-1-yl)methanone (2.96 g, 18.24 mmol) was added portionwise to a solution of 2-cyclohexyl-1-(methoxycarbonyl)piperidine-4-carboxylic acid (3.28 g, 12.16 mmol) (reference compound 35) in dry THF (20 mL) at 0° C. and put under nitrogen atmosphere. The ice bath was removed and the solution was stirred for 2 h at room temperature (flask 2). Then the contents of flask 1 was added to flask 2 and the resulting mixture was stirred overnight (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 water, 10% Na2CO3 and then dried over Na2SO4. The organic phase was washed with 0.1 M NaOH and dried again and evaporated to give a yellow oil. The compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, linear gradient heptanes/ethyl acetate 9:1 to 1:1 over 7CV. Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 6.9%) and cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.501, 49%) were isolated. Cis-isomer: 1H NMR (400 MHz, cdcl3) δ 0.90-1.29 (m, 5H), 1.26 (t, 3H), 1.37-2.05 (m, 10H), 2.57-2.70 (m, 1H), 2.85-3.02 (m, 1H), 3.48 (s, 2H), 3.67 (s, 3H), 3.71-3.84 (m, 1H), 3.86-3.99 (m, 1H), 4.18 (q, 2H). MS m/z 340 (M+H)+. Trans-isomer: 1H NMR (400 MHz, cdcl3) δ 0.80-1.30 (m, 5H), 1.26 (t, 3H), 1.33-1.90 (m, 9H), 1.96-2.12 (m, 1H), 2.69-2.86 (m, 2H), 3.46 (s, 2H), 3.67 (s, 3H), 3.84-4.33 (m, 2H), 4.21 (q, 2H). MS m/z 340 (M+H)+

Workup

  1. customThe ice bath was removed
  2. stirringthe solution was stirred for 2 h at room temperature (flask 2)
  3. additionThen the contents of flask 1 was added to flask 2
  4. stirringthe resulting mixture was stirred overnight (20 h)
  5. concentrationThe reaction mixture was concentrated
  6. extractionThe aqueous phase was extracted once with EtOAc
  7. washthe combined organic phase was washed with water, 10% Na2CO3
  8. dry with materialdried over Na2SO4
  9. washThe organic phase was washed with 0.1 M NaOH
  10. customdried again
  11. customevaporated
  12. customto give a yellow oil
  13. customThe compound was purified further via Biotage, 2 runs, SNAP 340 g KP-SIL, linear gradient heptanes/ethyl acetate 9:1 to 1:1 over 7CV

Sources & evidence

ORD record
ord-71a218e8d46246ee852772be0762728b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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