Hydrochloric Acid → (R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-one

HRID 1922180Notes

Reaction equation

HRID 1922180 reaction equation
[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N#N>CC(O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][CH:15]([CH3:16])[CH3:17])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 947NitrogenHCID 67492991(S)-1-benzyl-3-(3-methylbutanoyl)pyrrolidin-2-one

Product 1

HCID 59536630(R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-oneYield 100%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
65 °C

Procedure

Charge a 400 mL stainless steel autoclave vessel with a solution of (S)-1-benzyl-3-(3-methylbutanoyl)pyrrolidin-2-one (20 g, 77.12 mmoles) in IPA (250 mL), followed by 35% HCl (6% compared to the substrate, 4.63 mmoles, M=36.4 g/mol, d=1.18 g/mL, 0.408 mL). Purged with N2 gas (5ט50 PSI). Vent the vessel and quickly add (S)-Ru(OAc)2T-BINAP (250 mg, 0.2784 mmoles), while a stream of N2 flows over the top of the reaction mixture Immediately seal the autoclave and purge with N2 gas (5ט50 PSI). Purge the vessel with H2 gas (5×60 PSI) and then charge of the vessel with H2 gas (60 PSI). Stir the reaction mixture at 65° C. overnight (˜16-18 hours). The pressure of the vessel increases to ˜70 PSI during this time and the vessel is refilled with H2 gas as needed and not kept at a constant pressure of 60 PSI over the course of the reaction. Cool to room temperature and concentrate under reduced pressure to give crude (R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-one as a dark brown oil that was taken onto the next step without further purification (21.6 g, 82.6 mmoles, ˜95-97% ee, >100% yield). 1H NMR (300 MHz, CDCl3) δ 7.38-7.18 (m, 5H), 4.48 (s, 2H), 4.34-4.22 (m, 1H), 3.28-3.14 (m, 2H), 2.63 (td, 1H, J=2.93, 9.37 Hz), 2.47 (d, 1H, J=5.86 Hz), 2.12-1.70 (m, 3H), 1.54-1.38 (m, 1H), 1.24-1.10 (m, 1H), 0.95 (d, 3H, J=3.51 Hz), 0.93 (d, 3H, J=2.93 Hz). GC/MS=262 (M+1).

Workup

  1. customPurged with N2 gas (5ט50 PSI)
  2. customImmediately seal the autoclave
  3. custompurge with N2 gas (5ט50 PSI)
  4. customPurge the vessel with H2 gas (5×60 PSI)
  5. additioncharge of the vessel with H2 gas (60 PSI)
  6. temperatureThe pressure of the vessel increases to ˜70 PSI during this time
  7. additionthe vessel is refilled with H2 gas
  8. customnot kept at a constant pressure of 60 PSI over the course of the reaction
  9. temperatureCool to room temperature
  10. concentrationconcentrate under reduced pressure

Sources & evidence

ORD record
ord-277eaac48cce46dd99e28c3e9c8a7d95
Source dataset
uspto-grants-2012_05
Patent number
US08173821B2

Reaction notes

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