Diethyl Malonate → Ethyl 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetate

HRID 1091724Notes

Reaction equation

HRID 1091724 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]1)=[O:16].C(OCC)(=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.[Cu]I.C1(C2C=CC=CC=2O)C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10][C:9]=1[C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:23][CH3:24])[CH2:19][CH2:18]1)=[O:16]

Participants

7

Reactant 3

HCID 7761Diethyl MalonateHCID 10796Cesium carbonateHCID 57791814(2-Fluoro-5-iodophenyl)(4-methoxypiperidin-1-yl)methanone

Product 1

HCID 57791780Ethyl 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetateYield 215%

Reagents, catalysts & solvents 3

HCID 7017(1,1'-Biphenyl)-2-olCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
160 °C

Procedure

Cesium carbonate (2.308 g, 7.08 mmol) was added in one portion to (2-fluoro-5-iodophenyl)(4-methoxypiperidin-1-yl)methanone (41) (1.06 g, 2.92 mmol), diethyl malonate (1.329 mL, 8.76 mmol), 2-phenylphenol (0.099 g, 0.58 mmol) and copper(I) iodide (0.056 g, 0.29 mmol) in THF (10 mL) at 25° C. under nitrogen. The resulting mixture was stirred at 160° C. in the microwave reactor for 90 minutes. The reaction mixture was evaporated to dryness and redissolved in Et2O (200 mL), and washed sequentially with water (100 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (2.03 g, 72% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.25 (3H, t), 1.53-1.61 (1H, m), 1.67-1.74 (1H, m), 1.77-1.84 (1H, m), 1.89-1.97 (1H, m), 3.12-3.20 (1H, m), 3.36 (3H, s), 3.44-3.62 (3H, m), 3.59 (2H, s), 3.96-4.05 (1H, m), 4.15 (2H, q), 7.02-7.06 (1H, m), 7.26-7.33 (2H, m); m/z (LC-MS, ESI+), RT=1.08 (M+H 324.3).

Workup

  1. customThe reaction mixture was evaporated to dryness
  2. dissolutionredissolved in Et2O (200 mL)
  3. washwashed sequentially with water (100 mL) and saturated brine (50 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. customevaporated
  7. customto afford crude product
  8. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 50% ethyl acetate in isohexane
  9. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-b744206da36d481bad0e438a6d0bde81
Source dataset
uspto-grants-2012_03
Patent number
US08129380B2

Reaction notes

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