alpha-Bromo-o-chlorotoluene → N-[9-(2-Chloro-benzyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide

HRID 545507Notes

Reaction equation

HRID 545507 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>O1CCCC1>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([O:2][CH3:1])[CH:4]=2

Participants

5

Reactant 3

HCID 11905alpha-Bromo-o-chlorotolueneHCID 3251421Potassium bis(trimethylsilyl)amideHCID 59161196HCID 59161196, compound

Product 1

HCID 59161207N-[9-(2-Chloro-benzyl)-6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramideYield 69%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Dissolve N-(6-methoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 6) (100 mg, 0.35 mmol) in anhydrous tetrahydrofuran (4 mL) under nitrogen. Add dropwise potassium bis(trimethylsilyl)amide (0.77 mL, 0.385 mmol, 0.5N in toluene) and stir 25 min. Add slowly 2-chlorobenzylbromide (0.050 mL, 0.385 mmol) and stir at ambient temperature for 18 h. Quench with saturated ammonium chloride solution (0.5 mL) and dilute with a volume of dichloromethane and water (1 mL). Pass over a Varian Chem Elut column to remove aqueous portion and concentrate in vacuo. Alternatively, workup with ethyl acetate/water and dry over MgSO4. Purify the resulting residue by flash chromatography, eluting with dichloromethane with a gradient up to 10% ethyl acetate/dichloromethane to obtain 99 mg (69%) of a white solid. MS (ES): m/z 411, 413 (M+1); 1H NMR(DMSO-d6): δ 7.86 (d, 1H, J=7.5 Hz), 7.52 (d, 1H, J=8.4 Hz), 7.28 (t, 1H, J=7.7 Hz), 7.17 (m, 2H), 6.97 (d, 1H, J=2.2 Hz), 6.68 (dd, 1H, J=8.8, 2.2 Hz), 6.24 (d, 1H, J=7.9 Hz), 5.36 (s, 2H), 4.02 (m, 1H), 3.77 (s, 3H), 2.98 (dd, 1H, J=15.2, 5.1 Hz), 2.75-2.61 (m, 2H), 2.41 (m, 1H), 1.96 (m, 1H), 1.81 (m, 1H), 2.52 (m, 1H).

Workup

  1. stirringstir at ambient temperature for 18 h
  2. customQuench with saturated ammonium chloride solution (0.5 mL)
  3. additiondilute with a volume of dichloromethane and water (1 mL)
  4. customPass over a Varian Chem Elut column to remove aqueous portion
  5. concentrationconcentrate in vacuo
  6. dry with materialAlternatively, workup with ethyl acetate/water and dry over MgSO4
  7. customPurify the resulting residue by flash chromatography
  8. washeluting with dichloromethane with a gradient up to 10% ethyl acetate/dichloromethane

Sources & evidence

ORD record
ord-f351e1eaf08d4afdb582ec1328633908
Source dataset
uspto-grants-2011_05
Patent number
US07935722B2

Reaction notes

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