(2R)-3,6-diethoxy-2-(propan-2-yl)-2,5-dihydropyrazine → (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine

HRID 660380Notes

Reaction equation

HRID 660380 reaction equation
[CH2:1]([O:3][C:4]1[C@@H:5]([CH:13]([CH3:15])[CH3:14])[N:6]=[C:7]([O:10][CH2:11][CH3:12])[CH2:8][N:9]=1)[CH3:2].[Li]CCCC.Br[CH2:22][C@@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([O:25][CH2:24][C@H:23]([CH:33]([CH3:35])[CH3:34])[CH2:22][C@H:8]1[C:7]([O:10][CH2:11][CH3:12])=[N:6][C@H:5]([CH:13]([CH3:15])[CH3:14])[C:4]([O:3][CH2:1][CH3:2])=[N:9]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

5

Reactant 3

HCID 5325957(2R)-3,6-diethoxy-2-(propan-2-yl)-2,5-dihydropyrazineHCID 117159911-(((S)-2-(Bromomethyl)-3-methylbutoxy)methyl)benzeneHCID 178418339Butyllithium

Product 1

HCID 68784201(2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazineYield 82.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (15.4 g, 0.084 mol) in anhydrous THF (250 mL) at −78° C. was added dropwise 2.5 M n-BuLi in hexanes (34 mL, 0.085 mol) over 45 min. After stirring for 30 min at −78° C., a solution of (S)-((2-(bromomethyl)-3-methylbutoxy)methyl)benzene (15.6 g, 0.056 mol) in THF (100 L) was added dropwise over 30 min. The mixture was stirred for 2 h at −78° C. and then at −20° C. for 18 h. After evaporation, the residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine (0.5 L), dried over MgSO4, evaporated, and purified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane to give (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (18.5 g, 80%). 1H NMR (400 MHz, CDCl3): δ8.00 (s, 1H), 7.34-7.24 (m, 5H), 4.50 (s, 2H), 4.03 (m, 1H), 3.93 (m, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 3.54-3.42 (m, 2H), 2.27 (m, 1H), 1.94-1.88 (m, 1H), 1.80-1.61 (m, 1H), 1.47-1.42 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 0.88 (d, J=6.4 Hz, 3H), 0.80 (d, J=6.4 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H); MS: 403 (M++1).

Workup

  1. stirringThe mixture was stirred for 2 h at −78° C.
  2. waitat −20° C. for 18 h
  3. customAfter evaporation
  4. customthe residue was partitioned between H2O (200 mL) and EtOAc (3×200 mL)
  5. washThe combined organic layers were washed with brine (0.5 L)
  6. dry with materialdried over MgSO4
  7. customevaporated
  8. custompurified by flash chromatography on silica gel eluting with 1:25 EtOAc/hexane

Sources & evidence

ORD record
ord-f218c04165034674ab352d8f3c06d8b3
Source dataset
uspto-grants-2011_12
Patent number
US08084485B2

Reaction notes

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