Phenylacetylene → HCID 57330204, compound

HRID 2362456Notes

Reaction equation

HRID 2362456 reaction equation
Br[C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[O:11][C:10](=[O:21])[NH:9]2)[CH:5]=[N:6][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.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>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C@H:12]1[O:11][C:10](=[O:21])[NH:9][C@@H:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1

Participants

7

Reactant 3

HCID 10821PhenylacetyleneHCID 11776TriphenylphosphineHCID 69083834HCID 69083834, compound

Product 1

HCID 57330204HCID 57330204, compound

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8471TriethylamineSolvent

Procedure

To a stirred solution of optically enriched (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one (1.25 g, 3.25 mmol) in triethylamine (70 mL) was added ethynylbenzene (0.592 mL, 5.28 mmol), copper(I) iodide (67 mg, 0.352 mmol), and triphenylphosphine (653 mg, 2.464 mmol). Nitrogen was bubbled through the mixture for 10 minutes before adding dichlorobis(triphenylphosphine)-palladium(II) (202 mg, 0.282 mmol) with continued nitrogen gas bubbling. After an additional 10 minutes the reaction mixture was heated to reflux for 16 hours, cooled to ambient temperature, diluted with EtOAc, washed with water (3×), brine, dried over magnesium sulfate, and concentrated in vacuo. Column chromatography (25%-->40% EtOAc/Hex) provided optically enriched (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one which was separated by chiral SFC chromatography (Chiralcel OJ-H preparative column, 30×250 mm, 5 μm, Mobile Phase: 40% MeOH (0.1% DEA) in CO2 @ 150 Bar, Temp: 35° C., Flow rate: 70.0 mL/min. for 16 min, UV monitored @ 280 nM. tR=9.23 min) to provide (1.38 g, 2.99 mmol, 85% yield) of pure single enantiomer (4R,5R)-5-(2,5-difluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.77 (d, J=2.21 Hz, 1H) 8.57 (s, 1H) 8.56 (d, J=2.20 Hz, 1H) 8.07 (t, J=2.05 Hz, 1H) 7.58-7.66 (m, 2H) 7.44-7.52 (m, 3H) 7.39-7.45 (m, 1H) 7.28-7.39 (m, 2H) 5.67 (d, J=6.62 Hz, 1H) 5.04 (d, J=6.62 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm 157.28; 157.24 (d, J=240.70 Hz) 155.92 (d, J=245.20 Hz) 151.63; 147.70; 136.78; 135.02; 131.57; 129.43; 128.89; 126.63 (dd, J=14.99, 7.72 Hz) 121.51; 119.47; 117.83 (dd, J=23.60, 9.10 Hz) 117.50 (dd, J=24.50, 8.20 Hz); 114.60 (dd, J=26.34, 4.54 Hz); 92.86; 85.76; 78.12; 59.43; LCMS (ESI) m/z calcd for C22H15F2N2O2: 377.11. found 377.20 [M+H]+; HRMS (ESI) m/z calcd for C22H15F2N2O2: 377.1096. found 377.1096 [M+H]+.

Workup

  1. customNitrogen was bubbled through the mixture for 10 minutes
  2. custombubbling
  3. temperatureAfter an additional 10 minutes the reaction mixture was heated
  4. temperatureto reflux for 16 hours
  5. additiondiluted with EtOAc
  6. washwashed with water (3×), brine
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d69fce981ec4433189f405dcd0246ba1
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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