Acetic Acid → α-(3-Chlorophenyl)-5,5-dimethyl-2-pyrrolidinemethanol

HRID 990072Notes

Reaction equation

HRID 990072 reaction equation
N([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[CH3:8])=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C(O)(=O)C>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]([CH:7]2[CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]2)[OH:15])[CH:16]=[CH:17][CH:18]=1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 114773-ChlorobenzaldehydeHCID 184196512,2-Dimethyl-1-nitrosopyrrolidine

Product 1

HCID 18419650α-(3-Chlorophenyl)-5,5-dimethyl-2-pyrrolidinemethanol

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

35.4 ml (0.24 mols) of diisopropylamine are dissolved in 350 ml of tetrahydrofuran and cooled to −75° C. under nitrogen with a bath of dry ice and acetone. At this temperature, 180 ml (0.29 mols) of an approximately 1.6 molar solution of butyl lithium in hexane are added dropwise. By removing the cooling bath, the temperature is allowed to rise to −10° C. The solution of lithium-diisopropylamine thus obtained is again cooled to −78° C. This solution is mixed over the course of 20 minutes with 32 g (0.25 mols) of 1-nitroso-2,2-dimethylpyrrolidine and stirred for a further 10 minutes. Then, 35.2 g (0.25 mols) of 3-chlorobenzaldehyde are added dropwise over the course of 15 minutes, and the mixture is stirred for a further 3 hours at −75° C. To the resulting orange-coloured solution is then added dropwise, over the course of 20 minutes, a solution of 40 ml (0.7 mols) of glacial acetic acid in 80 ml of tetrahydrofuran. The reaction mixture which is now light yellow is warmed to room temperature by removing the cooling bath, and is then poured onto a mixture of 1 liter each of saturated sodium chloride solution and methyl chloride. After shaking out, the aqueous phase is separated and washed twice, each time with 200 ml of methylene chloride. The combined organic phases are washed with 200 ml of water, dried over sodium sulphate and the solvent residues are removed in a vacuum. The crystalline residue is dissolved whilst hot in a mixture of 180 ml of toluene and 270 ml of hexane. Upon cooling, the title substance is obtained in the form of white crystals having a m.p. of 143-144° C.

Workup

  1. stirringthe mixture is stirred for a further 3 hours at −75° C
  2. additionTo the resulting orange-coloured solution is then added dropwise, over the course of 20 minutes
  3. temperatureThe reaction mixture which is now light yellow is warmed to room temperature
  4. customby removing the cooling bath
  5. additionis then poured onto a mixture of 1 liter each of saturated sodium chloride solution and methyl chloride
  6. stirringAfter shaking out
  7. customthe aqueous phase is separated
  8. washwashed twice
  9. washThe combined organic phases are washed with 200 ml of water
  10. dry with materialdried over sodium sulphate
  11. customthe solvent residues are removed in a vacuum
  12. dissolutionThe crystalline residue is dissolved whilst
  13. additionhot in a mixture of 180 ml of toluene and 270 ml of hexane
  14. temperatureUpon cooling
  15. customthe title substance is obtained in the form of white crystals

Sources & evidence

ORD record
ord-bdb0f7b4d56b4a9f8cf67c7986859326
Source dataset
uspto-grants-2002_10
Patent number
US06458826B2

Reaction notes

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