Lithium diisopropylamide → 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one

HRID 1672719Notes

Reaction equation

HRID 1672719 reaction equation
[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH2:15][CH2:14][CH2:13][C:12]3=[O:16])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Br[CH2:26][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([O:34][CH3:35])=[CH:29][C:28]=1[Cl:36]>O1CCCC1>[Cl:33][C:32]1[CH:31]=[C:30]([O:34][CH3:35])[CH:29]=[C:28]([Cl:36])[C:27]=1[CH2:26][CH:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[C:12]1=[O:16]

Participants

5

Reactant 3

HCID 2724682Lithium diisopropylamideHCID 109002931-(1,4-Dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-oneHCID 592994792-(Bromomethyl)-1,3-dichloro-5-methoxybenzene

Product 1

HCID 578785993-(2,6-Dichloro-4-methoxy-benzyl)-1-(1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in tetrahydrofuran (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS (m+1) 414.

Workup

  1. custompurge
  2. customdid not reach above −67° C
  3. customremove the cold bath
  4. customreaction
  5. temperatureto warm over 3 hr
  6. customQuench
  7. customthe reaction with saturated aqueous ammonium chloride (100 mL)
  8. extractionextract with ethyl acetate (3×100 mL)
  9. dry with materialdry over anhydrous sodium sulfate
  10. customPurify on silica column
  11. washeluting with 8:2 hexanes

Sources & evidence

ORD record
ord-67c9f09a9b1c49a8ae8e214d6c6364a7
Source dataset
uspto-grants-2011_08
Patent number
US07998999B2

Reaction notes

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