1-Bromo-2,3-difluorobenzene → (6S,9R)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-9-[[tris(1-methylethyl)silyl]oxy]-5H-cyclohepta[b]pyridin-5-one

HRID 1099171Notes

Reaction equation

HRID 1099171 reaction equation
CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.[CH:33]([Si:36]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[O:37][C@H:38]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42](=[O:49])[CH2:41][CH2:40][CH2:39]1)([CH3:35])[CH3:34].Br[C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[F:64]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:63][C:59]1[C:58]([F:64])=[CH:57][CH:62]=[CH:61][C:60]=1[C@@H:41]1[CH2:40][CH2:39][C@@H:38]([O:37][Si:36]([CH:33]([CH3:35])[CH3:34])([CH:50]([CH3:52])[CH3:51])[CH:53]([CH3:55])[CH3:54])[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]1=[O:49]

Participants

7

Reactant 4

HCID 27332601-Bromo-2,3-difluorobenzeneHCID 27349382-(Dicyclohexylphosphino)-2'-methylbiphenylHCID 23676156Sodium t-butoxideHCID 57911448(R)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one

Product 1

HCID 57911475(6S,9R)-6-(2,3-Difluorophenyl)-6,7,8,9-tetrahydro-9-[[tris(1-methylethyl)silyl]oxy]-5H-cyclohepta[b]pyridin-5-one

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

See Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370. In an oven-dried 1 L flask was Sodium tert-butoxide (13.19 g, 137 mmol), PALLADIUM(II) ACETATE (0.948 g, 4.22 mmol), and 2-(Dicyclohexylphosphino)-2′-methylbiphenyl (1.539 g, 4.22 mmol) weighed in a nitrogen bag. (R)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (35.21 g, 106 mmol), Toluene (106 mL) (degassed in the original bottle by nitrogen gas), and 1-bromo-2,3-difluorobenzene (14.18 mL, 127 mmol) were added under nitrogen. The flask stirred at 80° C. in a pre-heated oil bath for 20 h. Volatiles were stripped off and the residue was partitioned between EtOAc (400 ml) and water (400 ml). The layers were separated. The aqueous layer was extracted with EtOAc (50 ml). The combined organic layer was washed with brine, dried and concentrated to a dark oil. It was passed through a plug of silica gel (loaded with CH2Cl2 and eluted with EtOAc/hexane up to 30% EtOAc). The crude product was obtained as a dark red oil (86% mass recovery). 1H NMR showed approximately 6/1 ratio of the desired trans isomer to the cis isomer. MS (ESI)[M+H+]=446.21.

Workup

  1. customIn an oven-dried 1 L flask was
  2. additionwere added under nitrogen
  3. customthe residue was partitioned between EtOAc (400 ml) and water (400 ml)
  4. customThe layers were separated
  5. extractionThe aqueous layer was extracted with EtOAc (50 ml)
  6. washThe combined organic layer was washed with brine
  7. customdried
  8. concentrationconcentrated to a dark oil
  9. washeluted with EtOAc/hexane up to 30% EtOAc)

Sources & evidence

ORD record
ord-d8a008a97cc64ff095fe1741b284eac9
Source dataset
uspto-grants-2012_03
Patent number
US08143403B2

Reaction notes

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