Ethyl 4-iodobenzoate → Ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate

HRID 1892702Notes

Reaction equation

HRID 1892702 reaction equation
I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18](Cl)=[O:19])[CH2:15]1>O1CCCC1.Cl.[Cu](I)I>[F:13][C:14]1([F:21])[CH2:17][CH:16]([C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[O:19])[CH2:15]1

Participants

6

Reactant 2

HCID 142891Ethyl 4-iodobenzoateHCID 83855003946488-78-4

Product 1

HCID 68157446Ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoateYield 16%

Reagents, catalysts & solvents 3

HCID 83717Copper iodideCatalystHCID 313Hydrochloric AcidSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

In a 3-neck flask at −30° C. containing ethyl 4-iodobenzoate (600 mg, 2.17 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise and then stirred at the same temperature for another 40 min. Copper iodide (124 mg, 0.650 mmol) was then added quickly in one portion. The mixture was brought to −15° C. for 20 min. to ensure the solid has dissolved. The reaction is then brought back to −40° C. Crude 3,3-difluorocyclobutanecarbonyl chloride (470 mg, 1.50 mmol pure) was then added and the reaction was then warmed to 0° C. over 1 h and then stirred at room temperature for 18 h. The mixture was then diluted with 1 N HCl and extracted three times with ethyl acetate. The combined organic layers were then washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide 680 mg of crude oil. Purification by silica gel flash chromatography (0-10% ethyl acetate in heptane) afforded impure ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate (130 mg, approximately 0.24 mmol pure) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=9.0 Hz, 2H), 7.18 (d, J=9.2 Hz, 2H), 4.39 (q, J=7.4 Hz, 2H), 3.34-3.15 (m, 1H), 3.12-2.78 (m, 4H), 1.40 (t, J=7.4 Hz, 3H).

Workup

  1. additionwas added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise
  2. waitThe mixture was brought to −15° C. for 20 min.
  3. dissolutionhas dissolved
  4. customis then brought back to −40° C
  5. stirringstirred at room temperature for 18 h
  6. extractionextracted three times with ethyl acetate
  7. washThe combined organic layers were then washed with brine
  8. dry with materialdried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto provide 680 mg of crude oil
  12. customPurification by silica gel flash chromatography (0-10% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-da8dfab7ac9d4eb885a7f492980238d7
Source dataset
uspto-grants-2013_08
Patent number
US08507533B2

Reaction notes

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