1H-1,2,4-Triazole, 1-methyl- → 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-1,2,4-triazol-5-yl) methanol

HRID 975677Notes

Reaction equation

HRID 975677 reaction equation
[CH3:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.C([Li])CCC.[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.CCCCCC>[CH2:12]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)[OH:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1

Participants

6

Reactant 3

HCID 224591H-1,2,4-Triazole, 1-methyl-HCID 50922891(2S,4R)-1-benzyl-2-formyl-4-(t-butyldimethylsilyloxy)pyrrolidineHCID 178418339Butyllithium

Product 1

HCID 544516311-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-1,2,4-triazol-5-yl) methanolYield 48.9%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1-methyl-1,2,4-triazole (3.12 g) in tetrahydrofuran (47 ml) at -70° C. was added dropwise n-butyllithium (1.6N) in hexane (25.5 ml) keeping the temperature below -60° C. After 15 minutes at -70° C., the mixture was warmed quickly to 0° C., stirred 5 minutes then recooled to -70° C. and stirred for 30 minutes. To the mixture was added a solution of (2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (10.0 g) in tetrahydrofuran (10 ml) keeping the temperature below -60° C. After 30 minutes the cooling bath was removed and the mixture was warmed to 0° C. over 30 minutes. After a further 2 hours the mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (×2). The combined organic layer was washed with brine and water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel (300 g, eluting with chloroform-methanol (30:1)) and then again on silica gel (300 g) eluting with ethyl acetate) to give 1-{(2S,4R)-1-benzyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-1,2,4-triazol-5-yl) methanol (6.16 g) (as a 4.3:1 mixture of diastereoisomers).

Workup

  1. customthe temperature below -60° C
  2. customthen recooled to -70° C.
  3. stirringstirred for 30 minutes
  4. customthe temperature below -60° C
  5. customAfter 30 minutes the cooling bath was removed
  6. temperaturethe mixture was warmed to 0° C. over 30 minutes
  7. customAfter a further 2 hours the mixture was quenched with saturated sodium bicarbonate solution
  8. extractionextracted with ethyl acetate (×2)
  9. washThe combined organic layer was washed with brine and water
  10. dry with materialdried over magnesium sulfate
  11. customevaporated under reduced pressure
  12. customchromatographed on silica gel (300 g, eluting with chloroform-methanol (30:1))
  13. washagain on silica gel (300 g) eluting with ethyl acetate)

Sources & evidence

ORD record
ord-c2522a2cd7514d7aa1ac2117a15d0329
Source dataset
uspto-grants-1997_03
Patent number
US05608056

Reaction notes

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