Tetrahydrofuran → 1-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one

HRID 629219Notes

Reaction equation

HRID 629219 reaction equation
[CH3:1][C:2]1([CH3:20])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][N:8]=2)[C:4](=[O:19])[CH2:3]1.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](I)[CH:27]=1.CCN(CC)CC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:27]=[C:26]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH2:6][C:2]([CH3:20])([CH3:1])[CH2:3][C:4]3=[O:19])=[N:8][CH:9]=2)[CH:25]=[N:24][CH:23]=1

Participants

10

Reactant 5

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 2724141Tetrabutylammonium FluorideHCID 184547783-Fluoro-5-iodopyridineHCID 575167294,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one

Product 1

HCID 534934901-[5-(5-Fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-oneYield 42%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6102075Dichlorobis(triphenylphosphine)palladiumCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

4,4-Dimethyl-1-(5-trimethylsilanylethynyl-pyridin-2-yl)-pyrrolidin-2-one (Example 37, step 2) (80 mg, 0.28 mmol) was dissolved in DMF (1 ml). 3-Fluoro-5-iodopyridine (87 mg, 0.39 mmol, 1.4 equiv.), Et3N (85 mg, 117 μl, 0.84 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride (10 mg, 14 μmol, 0.05 equiv.), triphenylphosphine (2 mg, 8.4 μmol, 0.03 equiv.) and copper(I)iodide (2 mg, 8.4 μmol, 0.03 equiv.) were added under nitrogen and the mixture was heated to 70° C. TBAF 1M in THF (300 μl, 0.3 mmol, 1.1 equiv.) was added dropwise in 20 minutes at 70° C. The reaction mixture was stirred for 30 minutes at 70° C. and evaporated with isolute to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column and eluting with heptane:ethyl acetate 100:0->0:100. The desired 1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-4,4-dimethyl-pyrrolidin-2-one (36 mg, 42% yield) was obtained as a white solid, MS: m/e=310.2 (M+H+).

Workup

  1. customevaporated with isolute to dryness
  2. customThe crude product was purified by flash chromatography with a 20 g silica gel column
  3. washeluting with heptane:ethyl acetate 100:0->0:100

Sources & evidence

ORD record
ord-e142f791ef2144a4b7d6483ba8231c76
Source dataset
uspto-grants-2016_04
Patent number
US09315498B2

Reaction notes

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