Reaction #2358543

Reaction equation

(S)-3-((R)-1-hydroxy-2-methylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester

p-chlorophenol

Diisopropyl azodicarboxylate

triphenylphosphine

→

(S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine-1-carboxylic acid t-butyl ester

Yield 10.8%

Solvents

—

Hexanes

—

hexanes

2-methyl-tetrahydrofuran

Conditions

Workup

1. 1
   Otherthe vessel purged with nitrogen
2. 2
   workup.STIRRINGthe resulting mixture was stirred at room temperature for 30 minutes
3. 3
   OtherThe phases were separated
4. 4
   Washthe organic layer was washed with 1.0 M NaOH in water (600 mL)
5. 5
   Washwashed with diluted saturated aqueous NaCl (20 mL)
6. 6
   Dryingdried over Na2SO4
7. 7
   Otherto yield the crude BOC-
8. 8
   workup.STIRRINGthe resulting mixture was stirred for 30 minutes
9. 9
   FiltrationSolids were filtered off
10. 10
    Otherto yield the crude BOC-
11. 11
    Otherwas then purified by silica gel chromatography (0-10-20% EtOAc in hexanes)

Procedure

(S)-3-((R)-1-hydroxy-2-methylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (35.0 g, 144 mmol, 1.0 eq.), triphenylphosphine (41.5 g, 158 mmol, 1.1 eq.), p-chlorophenol (37.0 g, 288 mmol, 2.0 eq.) and 2-methyl-tetrahydrofuran (300 mL) were combined and the vessel purged with nitrogen. Diisopropyl azodicarboxylate (31.2 mL, 1.1 eq.) was added slowly at room temperature over 2 hours. The mixture was then stirred at room temperature overnight. Hexanes (600 mL) were added and the resulting mixture was stirred at room temperature for 30 minutes. The phases were separated and the organic layer was washed with 1.0 M NaOH in water (600 mL), washed with diluted saturated aqueous NaCl (20 mL), then dried over Na2SO4 to yield the crude BOC-protected intermediate. Additional hexanes (50 mL) were added and the resulting mixture was stirred for 30 minutes. Solids were filtered off to yield the crude BOC-protected intermediate as a thick oil, which was then purified by silica gel chromatography (0-10-20% EtOAc in hexanes) to yield (S)-3-[(S)-1-(4-chlorophenoxy)-2-methylpropyl]pyrrolidine-1-carboxylic acid t-butyl ester (5.5 g).

Source