Methanol → Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate

HRID 1487841Notes

Reaction equation

HRID 1487841 reaction equation
[I:1]N1C(=O)CCC1=O.[CH:9]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1.CO>S(=O)(=O)(O)O>[CH:9]1([C:13]2[C:22]([I:1])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:10][CH2:11][CH2:12]1

Participants

5

Reactant 3

HCID 887MethanolHCID 120273N-IodosuccinimideHCID 10488418Methyl 4-cyclobutyl-2-methylbenzoate2×

Product 1

HCID 68288363Methyl 4-cyclobutyl-5-iodo-2-methylbenzoateYield 81%

Reagents, catalysts & solvents 1

HCID 1118Sulfuric AcidSolvent

Conditions

Temperature
0 °C

Procedure

N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portion-wise to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound 6.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and at RT for 2 hours, upon where the mixture turned very thick. The mixture was again cooled to 0° C. and MeOH (30 mL) was slowly and carefully added. The mixture was heated at 60° C. for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was poured onto ice water (100 mL). The mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, then aqueous 1M NaHCO3 (note-significant gas evolution), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1) to yield the title compound as a light yellow oil (4.17 g, 81%). 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H), 1.82-1.79 (m, 1H).

Workup

  1. temperatureThe mixture was again cooled to 0° C.
  2. additioncarefully added
  3. temperatureThe mixture was heated at 60° C. for 2 hours
  4. temperatureAfter cooling to room temperature
  5. customthe solvent was removed under reduced pressure
  6. additionthe residue was poured onto ice water (100 mL)
  7. extractionThe mixture was extracted with EtOAc (2×)
  8. washThe combined organic layers were washed with brine
  9. dry with materialaqueous 1M NaHCO3 (note-significant gas evolution), dried (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe residue was purified by silica gel column chromatography (hexanes:EtOAc 30:1 to 20:1)

Sources & evidence

ORD record
ord-94cd56017ac3468bb74b1df2fc5fb483
Source dataset
uspto-grants-2016_08
Patent number
US09428502B2

Reaction notes

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