Reaction #50037

Reaction equation

5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone

product

5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone

borane THF

→

title compound

3-Methyl-5-(1-methyl-2(S)-pyrrolidinyl)isoxazole

Solvents

THF

Conditions

Workup

1. 1
   TemperatureThe reaction mixture was heated
2. 2
   Temperatureat reflux for two hours
3. 3
   OtherAfter removal of THF under vacuum
4. 4
   workup.ADDITIONa solution of formaldehyde (10.0 mL) and formic acid (5.0 mL) was carefully added
5. 5
   Temperaturethe reaction mixture was refluxed for one hour
6. 6
   workup.ADDITIONEthyl acetate (300 mL) was added
7. 7
   workup.ADDITIONfollowed by the addition of sodium carbonate until basic
8. 8
   OtherThe organic layer was decanted
9. 9
   Washthe residue was washed with ethyl acetate (4×20 mL)
10. 10
    DryingThe combined organic solvents were dried over sodium carbonate
11. 11
    OtherThe solvent was evaporated
12. 12
    workup.DISTILLATIONthe residue was distilled (bp. ~150° C./~50 mm Hg)

Procedure

To a solution of crude 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone (5.33 g, 32.1 mmol, the product of step 13b) in THF (50 mL) was added borane-THF (99.5 mL, 1.0M, 99.5 mmol) slowly at room temperature. The reaction mixture was heated at reflux for two hours. After removal of THF under vacuum, a solution of formaldehyde (10.0 mL) and formic acid (5.0 mL) was carefully added, and the reaction mixture was refluxed for one hour. Ethyl acetate (300 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, and the residue was washed with ethyl acetate (4×20 mL). The combined organic solvents were dried over sodium carbonate. The solvent was evaporated, and the residue was distilled (bp. ~150° C./~50 mm Hg) to give the title compound (3.12 g, 59%; 24% overall yield). The compound was further purified by HPLC chromatography (CHCl3 /MeOH, 20:1 and 10:1). HPLC (analytical Chiralark OD column) analysis indicated >99% ee. [α]D23° =-13.1° (c 0.9, MeOH). MS (DCl/NH3) m/e: 153 (M+H)+. 1H NMR (CDCl3) δ 1.80-2.00 (m, 3H), 1.99 (br s, 1H, NH), 2.14-2.21 (m, 1H), 2.28 (s, 3H), 2.96-3.16 (m, 2H), 4.32 (dd, 1H), 5.95 (s, 1H).

Source