(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine → (2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

HRID 451805

Reaction equation

HRID 451805 reaction equation
[CH:1]([C@@H:4]1[C:9]([O:10][CH3:11])=[N:8][CH2:7][C:6]([O:12][CH3:13])=[N:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:19]([Si:23]([O:26][C@@H:27]1[CH2:31][C@@H:30]([CH2:32]I)[CH2:29][C@H:28]1[F:34])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[Si:23]([O:26][C@H:27]1[C@H:28]([F:34])[CH2:29][C@H:30]([CH2:32][C@H:7]2[C:6]([O:12][CH3:13])=[N:5][C@H:4]([CH:1]([CH3:3])[CH3:2])[C:9]([O:10][CH3:11])=[N:8]2)[CH2:31]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]

Participants

5

Reactant 3

HCID 736066(R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazineHCID 59382951Rel-tert-butyl(((1R,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyl)oxy)dimethylsilaneHCID 178418339Butyllithium

Product 1

HCID 59201654(2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazineYield 100.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of (R)-2-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.2 g, 1.5 equiv.) in dry THF (30 mL) was cooled to −78° C. n-BuLi (1.6 M in Hexane, 4.08 mL, 1.5 equiv.) was added dropwise. After stirring 1 h at −78° C., a solution of (±)-tert-butyl((1r,2R,4R)-2-fluoro-4-(iodomethyl)cyclopentyloxy)dimethylsilane (1.56 g, 4.36 mmol) in dry THF (8 mL) was added dropwise. The mixture was stirred another 2 h at −78° C. The mixture was warmed up to rt slowly, quenched by sat. NH4Cl solution (30 mL), extracted by diethyl ether (2×150 mL). The combined organic layers were washed by brine (30 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (40 g column, 0˜25% EtOAc in Hexanes) to afford (2S,5R)-2-(((1r*,3R*,4R*)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (1.81 g, quant. yield) as a clear oil. MS ESI +ve m/z 415 (M+1).

Workup

  1. additionwas added dropwise
  2. stirringThe mixture was stirred another 2 h at −78° C
  3. temperatureThe mixture was warmed up to rt slowly
  4. customquenched by sat. NH4Cl solution (30 mL)
  5. extractionextracted by diethyl ether (2×150 mL)
  6. washThe combined organic layers were washed by brine (30 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationAfter filtration and concentration
  9. customthe residue was purified by ISCO (40 g column, 0˜25% EtOAc in Hexanes)

Sources & evidence

ORD record
ord-aad48de85c9b43afa4e0ddf68c77e349
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Linked notes

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