(2S)-2,5-Dihydro-2-isopropyl-3,6-dimethoxypyrazine → (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)-5-isopropylpyrazine

HRID 1919480Notes

Reaction equation

HRID 1919480 reaction equation
[CH3:1][O:2][C:3]1[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.[F:19][C:20]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>O1CCCC1>[CH3:10][O:9][C:6]1[C@@H:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:20]=2[F:19])[N:8]=[C:3]([O:2][CH3:1])[C@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1

Participants

5

Reactant 3

HCID 736065(2S)-2,5-Dihydro-2-isopropyl-3,6-dimethoxypyrazineHCID 27375702-Fluoro-4-(trifluoromethyl)benzyl bromideHCID 178418339Butyllithium

Product 1

HCID 20628238(2R,5S)-2,5-dihydro-3,6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)-5-isopropylpyrazine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 3.32 g (18 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran at −70° C. was added 12 mL (19 mmol) of a 1.6M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction to ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brine, dried, and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded 5.5 g of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.33-7.25 (m, 3H), 4.35-4.31 (m, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 3.60 (t, 1H, J=3.4 Hz), 3.33 (dd, 1H, J=4.6, 13.5 Hz), 3.03 (dd, 1H, J=7, 13.5 Hz), 2.25-2.15 (m, 1H), 1.0 (d, 3H, J=7 Hz), 0.66 (d, 3H, J=7 Hz).

Workup

  1. stirringstirring
  2. waitwas continued for 3 h
  3. temperaturebefore warming
  4. customthe reaction to ambient temperature
  5. customThe reaction was quenched with water
  6. concentrationconcentrated in vacuo
  7. extractionextracted with ethyl acetate
  8. washThe combined organic phase was washed with brine
  9. customdried
  10. concentrationconcentrated in vacuo
  11. customPurification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-1f8dc2bf66014063b1ce02f630a842e9
Source dataset
uspto-grants-2012_05
Patent number
US08168637B2

Reaction notes

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