Tetrabutylammonium Fluoride → (6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol

HRID 1879372Notes

Reaction equation

HRID 1879372 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([OH:31])[CH2:19][CH2:18][C@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:31])[CH2:19][CH2:18][C@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium Fluoride2×HCID 67115983(6R,95)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol

Product 1

HCID 58467984(6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diolYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

In a 250 mL round-bottom flask was dissolved (6R,95)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-6-ol (977 mg, 2.183 mmol) in tetrahydrofuran (10 mL) to give a colorless solution. TBAF (4.80 mL, 4.80 mmol) was added, and the mixture was stirred at 50° C. overnight for 16 h. LCMS indicated good conversion with some SM left. Another 0.2 equiv of TBAF was added and the reaction continued at 50° C. for 2 h. Tetrahydrofuran was removed and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with sodium sulfate, and concentrated to give a tan oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product as a white solid (458 mg, 72%). MS(ESI)[M+H+]=292.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.05 (d, J=3.78 Hz, 1H) 7.37 (d, J=7.55 Hz, 1H) 7.06-7.21 (m, 1H) 6.81-7.05 (m, 3H) 5.63 (br. s., 1H) 4.82-4.97 (m, 1H) 3.68-4.11 (m, 2H) 3.00 (d, J=14.35 Hz, 1H) 2.77 (t, J=10.58 Hz, 1H) 2.13 (t, J=11.21 Hz, 1H) 1.87-2.03 (m, 1H) 1.69-1.86 (m, 1H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.37 (br. s., 1F) −137.99 (d, J=15.52 Hz, 1F).

Workup

  1. customto give a colorless solution
  2. waitleft
  3. waitthe reaction continued at 50° C. for 2 h
  4. customTetrahydrofuran was removed
  5. customthe residue was partitioned between water and ethyl acetate
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted with ethyl acetate
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried with sodium sulfate
  10. concentrationconcentrated
  11. customto give a tan oil
  12. customPurification by FCC up to 10% methanol/methylene chloride

Sources & evidence

ORD record
ord-0c3233b2b0e849218cd9e37aa8c942de
Source dataset
uspto-grants-2012_11
Patent number
US08314117B2

Reaction notes

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