4-Bromo-1,2-dichlorobenzene → 9-(3,4-Dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester

HRID 419274Notes

Reaction equation

HRID 419274 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:28][CH2:29][C:30]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=3)([OH:33])[CH2:31][CH2:32]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]

Participants

5

Reactant 3

HCID 290134-Bromo-1,2-dichlorobenzeneHCID 51072194tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylateHCID 178418339Butyllithium

Product 1

HCID 666507759-(3,4-Dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl esterYield 35.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

1-Bromo-3,4-dichlorobenzene (1.35 g, 5.98 mmol) in THF (10 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes, 4 mL) at −78° C. The mixture was stirred for 40 min at −78° C. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3.74 mmol) in THF (10 mL) was added drop-wise and the mixture was stirred for 1 h at −78° C. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted twice with diethyl ether. The combined organic phase was washed with brine dried (sodium sulfate), filtered and evaporated to give 2.2 g of crude material. Precipitation in heptane and diethyl ether gave 547 mg of 9-(3,4-dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-ESI-HRMS of [M+H]+ shows 296.0983 Da. Calc. 296.09728 Da, dev. 3.4 ppm.

Workup

  1. stirringthe mixture was stirred for 1 h at −78° C
  2. customThe reaction was quenched with aqueous ammonium chloride
  3. extractionthe aqueous layer was extracted twice with diethyl ether
  4. washThe combined organic phase was washed with brine
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. customevaporated
  8. customto give 2.2 g of crude material
  9. customPrecipitation in heptane

Sources & evidence

ORD record
ord-a109325ed10945438551e83f508937fc
Source dataset
uspto-grants-2012_01
Patent number
US08093388B2

Reaction notes

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