Diisopropylamine → tert-Butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate

HRID 626408Notes

Reaction equation

HRID 626408 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[F:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[F:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 129227103-Bromo-4-fluorobenzyl BromideHCID 13676038tert-Butyl cyclopropanecarboxylateHCID 178418339Butyllithium

Product 1

HCID 58136672tert-Butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-50 °C

Procedure

Under argon, 199.5 ml (1.42 mol) of diisopropylamine were initially charged in 1300 ml of dry THF and cooled to −50° C. 569.1 ml (1.42 mol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 161.9 g (1.14 mol) of tert-butyl cyclopropanecarboxylate in 380 ml THF was added to the reaction solution, with the temperature being kept below −60° C. After 4 h of stirring at −78° C., a solution of 262 g (0.95 mol) of 2-bromo-4-(bromomethyl)-1-fluorobenzene in 480 ml of THF was added, the temperature again being kept below −60° C. The reaction mixture was then slowly warmed to RT overnight, after which 1.5 liters of saturated aqueous ammonium chloride solution and 3.0 liters of ethyl acetate were carefully added. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 3 kg of silica gel (mobile phase cyclohexane/dichloromethane 9:1, then 5:1). 189.9 g (50.4% of theory) of the title compound were thus obtained.

Workup

  1. temperatureThe resulting mixture was warmed to 0° C.
  2. temperaturecooled to −70° C
  3. custombeing kept below −60° C
  4. customagain being kept below −60° C
  5. temperatureThe reaction mixture was then slowly warmed to RT overnight
  6. customAfter phase separation
  7. extractionthe aqueous phase was extracted with ethyl acetate
  8. washThe combined organic phases were washed with saturated sodium chloride solution
  9. dry with materialdried over magnesium sulphate
  10. concentrationconcentrated under reduced pressure
  11. customThe crude product was purified by chromatography on 3 kg of silica gel (mobile phase cyclohexane/dichloromethane 9:1

Sources & evidence

ORD record
ord-ca1c38fb101c44a0a060d25e406e58d6
Source dataset
uspto-grants-2016_04
Patent number
US09309198B2

Reaction notes

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