Triphenylphosphine → (5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine

HRID 409035Notes

Reaction equation

HRID 409035 reaction equation
C1C(=O)N([Cl:8])C(=O)C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=1[C@@H:36]1[CH2:46][CH2:45][C@@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[C:39]2=[N:40][CH:41]=[CH:42][CH:43]=[C:38]2[C@H:37]1O>O1CCCC1>[Cl:8][C@H:37]1[C:38]2[C:39](=[N:40][CH:41]=[CH:42][CH:43]=2)[C@H:44]([O:47][Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:46][C@H:36]1[C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[F:28]

Participants

5

Reactant 3

HCID 11776TriphenylphosphineHCID 31398ChlorosuccinimideHCID 57911423(5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol

Product 1

HCID 67115927(5R,6S,9R)-5-chloro-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridineYield 83%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

In an oven-dried 250 mL round-bottom flask was suspended NCS (0.751 g, 5.62 mmol) in tetrahydrofuran (15 mL). Triphenylphosphine (1.475 g, 5.62 mmol) was added. After stirring under nitrogen for 5 min, (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.007 g, 2.250 mmol) was added in one portion to the gray suspension. The resulting reddish suspension was stirred at room temperature. The solids gradually dissolved to give a tan solution. After 5 h, LCMS indicated complete conversion. Tetrahydrofuran was removed in vacuo and the remaining red oil was directly purified by ISCO (240 g silica column) up to 60% ethyl acetate/hexane. Pure ethyl acetate eluted the non polar component and the product was eluted by 10% methanol (with 2.0M NH4OH) in methylene chloride. The product fractions were combined and re-purified by FCC up to 50% ethyl acetate/hexane to afford the desired product as a colorless oil (869 mg, 83%). MS (ESI) [M+H+]=466.22; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (d, J=3.53 Hz, 1H) 7.63 (br. s., 1H) 7.20 (dd, J=7.68, 4.91 Hz, 1H) 7.01-7.15 (m, 1H) 6.90-7.01 (m, 1H) 6.66-6.90 (m, 1H) 5.55-5.85 (m, 1H) 5.40-5.56 (m, 1H) 3.96-4.33 (m, 1H) 2.33 (br. s., 3H) 2.09-2.20 (m, 1H) 1.14-1.23 (m, 3H) 1.04-1.14 (m, 9H) 1.01 (d, J=7.30 Hz, 9H).

Workup

  1. customIn an oven-dried 250 mL round-bottom flask was suspended
  2. stirringThe resulting reddish suspension was stirred at room temperature
  3. dissolutionThe solids gradually dissolved
  4. customto give a tan solution
  5. waitAfter 5 h
  6. customTetrahydrofuran was removed in vacuo
  7. customthe remaining red oil was directly purified by ISCO (240 g silica column) up to 60% ethyl acetate/hexane
  8. washPure ethyl acetate eluted the non polar component
  9. washthe product was eluted by 10% methanol (with 2.0M NH4OH) in methylene chloride
  10. customre-purified by FCC up to 50% ethyl acetate/hexane

Sources & evidence

ORD record
ord-4772e78104f1465ca954586108ed4c75
Source dataset
uspto-grants-2014_06
Patent number
US08759372B2

Reaction notes

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