Triphenylphosphine → n-Tert-butyl-1-cyano-n-methyl-1-[(r)-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1h-indol-5-yl]methanesulfonamide

HRID 651713Notes

Reaction equation

HRID 651713 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].[C:22]([N:26]([CH3:33])[S:27]([CH2:30][C:31]#[N:32])(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23].[H-].[Na+].Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH:41]=[C:40]2[CH2:56][C@H:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH3:62]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:22]([N:26]([CH3:33])[S:27]([CH:30]([C:31]#[N:32])[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[N:42]([S:46]([C:49]1[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH:41]=[C:40]2[CH2:56][C@H:57]1[CH2:61][CH2:60][CH2:59][N:58]1[CH3:62])(=[O:28])=[O:29])([CH3:25])([CH3:24])[CH3:23]

Participants

9

Reactant 5

HCID 11776TriphenylphosphineHCID 24758Sodium hydrideHCID 4311764Sodium borohydrideHCID 21709114N-tert-butyl-1-cyano-N-methylmethanesulfonamideHCID 54296311(R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indole

Product 1

HCID 53762173n-Tert-butyl-1-cyano-n-methyl-1-[(r)-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1h-indol-5-yl]methanesulfonamideYield 45%

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent2×

Conditions

Temperature
2.5 °C

Procedure

To a stirred suspension of dichlorobis(triphenylphosphine)palladium (II) (704 mg, 1 mmol) and triphenylphosphine (525 mg, 2 mmol) in ethyleneglycol dimethylether (5 ml) at ambient temperature under an atmosphere of nitrogen was added sodium borohydride (38 mg, 1 mmol) in one portion. The green slurry was stirred for 5 min, then N-tert-butyl-cyano-N-methylmethanesulfonamide (from step (c), 1.04 g, 5.4 mmol) was added in one portion. The green slurry was then cooled to 0-5° C. and sodium hydride (60% dispersion in mineral oil) (441 mg, 11 mmol) was added portionwise, maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 10 min period, before a solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1-tosyl-1H-indole (from step (d), 2.24 g, 5 mmol) in ethyleneglycol dimethyl ether (15 ml) was added dropwise. The brown slurry was then warmed to reflux. Reflux was maintained for 1.5 hr after which time the dark brown solution was cooled to ambient temperature. The reaction mixture was then poured into water (20 ml) and extracted with ethyl acetate (3×25 ml). The organic extracts were combined and evaporated in vacuo to yield a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitle compound (1.23 g, 45%) as a golden oil.

Workup

  1. temperaturemaintaining the temperature below 5° C
  2. additionwas added dropwise
  3. temperatureThe brown slurry was then warmed to reflux
  4. temperatureReflux
  5. temperaturewas maintained for 1.5 hr after which time the dark brown solution
  6. temperaturewas cooled to ambient temperature
  7. extractionextracted with ethyl acetate (3×25 ml)
  8. customevaporated in vacuo
  9. customto yield a brown oil
  10. customThis was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant)

Sources & evidence

ORD record
ord-a5a63d26e1d640fcbcc119f9b33a24a1
Source dataset
uspto-grants-2001_08
Patent number
US06281357B1

Reaction notes

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