Iodine → HCID 59382885, compound

HRID 2266238Notes

Reaction equation

HRID 2266238 reaction equation
[Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1CC1CC1.CON(C)[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)=[O:20].[CH2:35]1[CH2:39][O:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:39][O:38][C:6]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=2[C:19]([C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:22]2)=[O:20])[CH2:36][CH2:37]1

Participants

6

Reactant 5

HCID 807Iodine2×HCID 8028Tetrahydrofuran2×HCID 5462224Magnesium2×HCID 30025965(R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylateHCID 67191843HCID 67191843, compound

Product 1

HCID 59382885HCID 59382885, compoundYield 70%

Procedure

A 50 mL three-necked flask was charged with magnesium turning (240 mg, 10 mmol) and a small crystal of iodine. The flash was evacuated and refilled with N2. A portion of a solution of 1-bromo-2-cyclopropylmethyl-3-fluoro-benzene (2.1 g, 8.57 mmol) in dry THF (10 mL) was added dropwise to trigger the reaction. When the color of iodine had disappeared, the residual solution was added dropwise slowly. The mixture was stirred under reflux for 2.5 h and most of magnesium was consumed. The resulting Grignard reagent was used for the next step. To another 100-mL three-necked flask was added (R)-tert-butyl 3-(methoxy(methyl)-carbamoyl)piperidine-1-carboxylate (1.55 g, 5.7 mmol) and THF (15 mL). The flask was evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent prepared above (10 mL) was added slowly. The reaction mixture was stirred at −20 to −10° C. for 2.5 h. The mixture was quenched with sat'd aq NH4Cl (20 mL), extracted with EtOAc (3×), and the combined organic layers were dried over Na2SO4. Solvent removal and flash column chromatography, eluting with 5% EtOAc/PE afforded (R)-tert-butyl 3-(2-(cyclopropylmethoxy)-3-fluorobenzoyl)piperidine-1-carboxylate (1.5 g, 70%). 1H NMR (400 MHz, CDCl3): 0.27 (m, 2H), 0.57 (m, 2H) 1.20 (m, 1H), 1.43 (s, 9H), 1.60-1.51 (m, 4H), 1.73 (m, 1H), 2.02 (m, 1H), 2.79 (m, 1H), 3.47 (m, 1H), 3.98 (m, 3H), 4.20 (m, 1H), 7.04 (m, 1H), 7.20 (m, 2H). MS (E/Z): 378 (M+H+).

Workup

  1. customThe flash was evacuated
  2. additionrefilled with N2
  3. customthe reaction
  4. additionthe residual solution was added dropwise slowly
  5. customwas consumed
  6. customThe flask was evacuated
  7. additionrefilled with N2
  8. temperatureThe mixture was cooled in a dry ice-acetone bath
  9. customthe Grignard reagent prepared above (10 mL)
  10. additionwas added slowly
  11. stirringThe reaction mixture was stirred at −20 to −10° C. for 2.5 h
  12. customThe mixture was quenched with sat'd aq NH4Cl (20 mL)
  13. extractionextracted with EtOAc (3×)
  14. dry with materialthe combined organic layers were dried over Na2SO4
  15. customSolvent removal and flash column chromatography
  16. washeluting with 5% EtOAc/PE

Sources & evidence

ORD record
ord-fcdb44e2af0842c188c564e44c2f0a9f
Source dataset
uspto-grants-2010_12
Patent number
US07858624B2

Reaction notes

Loading…