Ammonium Chloride → (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine

HRID 1471646Notes

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.[Li]CCCC.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([CH2:27]Br)[CH:21]=1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[CH2:27][C@H:7]1[C:6]([O:9][CH3:10])=[N:5][C@H:4]([CH:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8]1

Participants

Conditions

Temperature: -78 °C

Procedure

To (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (2 mL, 11.03 mmol) in THF (90 mL) at −78° C. was added n-BuLi (1.6 M in hexanes solution, 7.5 mL, 12 mmol). After stirring for 30 min, 1-bromo-3-(bromomethyl)-5-fluorobenzene (2.68 g, 10 mmol) in THF (10 mL) was added dropwise over 30 min. The temperature was maintained at −78° C. for 30 min then allowed to warm to ambient temperature. After stirring for 16 h, saturated aqueous NH4Cl (30 mL) was added followed by dilution with EtOAc and H2O. The THF was removed in vacuo and the remaining organics were separated and dried over sodium sulfate. After removal of solvent, the crude product was purified by silica gel chromatography to provide (2S,5R)-2-(3-bromo-5-fluorobenzyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (3.17 g, 77%). MS (m/z) 371 [M+H]+.

Workup

temperatureto warm to ambient temperature
stirringAfter stirring for 16 h
customThe THF was removed in vacuo
customthe remaining organics were separated
dry with materialdried over sodium sulfate
customAfter removal of solvent
customthe crude product was purified by silica gel chromatography

Sources & evidence

ORD record: ord-75900fdfa84f4de8bf5c6ffd0b1984da
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09012441B2

Reaction notes

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