Methanol → 1-(4-Fluoro-phenyl)4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazole-5-carbaldehyde

HRID 1723911

Reaction equation

HRID 1723911 reaction equation
[Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][C:53](=O)[C:46]4([CH3:55])[CH2:45][C:44]=3[CH:43]=[N:42]2)=[CH:37][CH:36]=1.CO>C1COCC1.Cl.O>[F:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[C:49]3[CH:48]=[C:47]4[CH2:50][CH2:51][CH2:52][CH:53]([CH:2]=[O:3])[C:46]4([CH3:55])[CH2:45][C:44]=3[CH:43]=[N:42]2)=[CH:39][CH:40]=1

Participants

8

Reactant 4

HCID 887MethanolHCID 2723798Methoxymethyl-triphenylphosphonium chlorideHCID 3251421Potassium bis(trimethylsilyl)amideHCID 226059921-(4-Fluoro-phenyl)-4a-methyl-1,4,4a,6,7,8-hexahydro-benzo[f]indazol-5-one

Product 1

HCID 226059711-(4-Fluoro-phenyl)4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo[f]indazole-5-carbaldehydeYield 70.2%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
0 °C

Procedure

To a cold (−30° C.) solution of (methoxymethyl)triphenylphosphonium chloride (13.85 g, 40.4 mmol) in THF (40 mL), was added KHMDS (0.5M in toluene, 70.8 mL, 35.4 mmol). The resulting red solution was stirred at 0° C. for 15 minutes before being treated with a solution of 205 (3 g, 10.1 mmol) in THF (40 mL). The mixture was stirred at room temperature for 24 hours. A solution of methanol in THF (1:1, 40 mL) and 4 N HCl (30 mL) was added to the mixture at 0° C. The resulting solution was allowed to stir at room temperature for 26 hours and was them poured into water (30 mL) and extracted with ether (4×50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. Purification of the residue by flash chromatography on silica gel (0-50% ethyl acetate-hexanes) gave 2.2 g (70%) of 207 as a yellow solid. A small portion was further purified via bisulfite addition for characterization. 1H NMR (CDCl3) δ 1.12 (s, 3H), 1.35-1.49 (m, 1H), 1.67-1.8 (m, 1H), 1.87-2.0 (m, 2H), 2.28-2.48 (m, 3H), 2.9 (d, J=16.0 Hz, 1H), 3.1 (d, J=16.0 Hz, 1H), 6.18 (s, 1H), 7.16 (t, J=8.5 Hz, 2H), 7.42-7.48 (m, 3H), 9.90 (d, J=2.0 Hz, 1H); 13C NMR (CDCl3) 203.99, 162.64, 160.18, 147.26, 137.77, 136.35, 135.65, 135.62, 125.36, 125.32, 125.24, 116.09, 115.87, 113.36, 109.93, 60.78, 39.90, 34.55, 32.10, 24.52, 22.62, 18.96.

Workup

  1. stirringThe mixture was stirred at room temperature for 24 hours
  2. stirringto stir at room temperature for 26 hours
  3. extractionextracted with ether (4×50 mL)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customPurification of the residue by flash chromatography on silica gel (0-50% ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-2bfd316c3636451aa104f707a9c29ff5
Source dataset
uspto-grants-2009_02
Patent number
US07485660B2

Linked notes

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