2,6-Lutidine → 4-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrile

HRID 273012Notes

Reaction equation

HRID 273012 reaction equation
[N:1]1[C:6](C)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][S:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].ClCCCN1CCCC1>C(#N)C.CN(C)C=O>[N:1]1([CH2:2][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

8

Reactant 5

HCID 79372,6-LutidineHCID 9845Trifluoroacetic anhydrideHCID 11430Potassium CarbonateHCID 113210281-(3-Chloropropyl)-pyrrolidineHCID 685781544-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile

Product 1

HCID 598374854-{4-[(3-pyrrolidin-1-ylpropyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrileYield 86%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Procedure

2,6-Lutidine (3.33 ml, 28.6 mmol) was added to a solution of 4-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile (2.3 g, 9.23 mmol) in acetonitrile (70 ml). The mixture was cooled in an ice-acetone bath and trifluoroacetic anhydride (3.87 ml, 27.69 mmol) added slowly. The solution was stirred at this temperature under nitrogen for 3 hours. The reaction mixture was then concentrated in vacuo and the residue taken up in methanol (7 ml). Triethylamine (7 ml) was added at 0° C. and the mixture stirred at 0° C. for 30 minutes. N,N-Dimethylformamide (10 ml) was added at 0° C., followed by potassium carbonate (2.8 g, 20.31 mmol) and 1-(3-chloro-propyl)-pyrrolidine (2.72 g, 18.46 mmol) in N,N-dimethylformamide (10 ml). The mixture was then warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×150 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 95:5:0.5 by volume) to provide the title compound (2.62 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3) δ 1.77-1.80 (m, 4H), 1.84-1.91 (m, 2H), 2.01-2.14 (m, 4H), 2.48-2.52 (m, 4H), 2.58 (t, 2H), 2.99 (t, 2H), 3.89 (t, 2H), 4.06-4.10 (m, 2H), 7.34-7.39 (m, 4H). LRMS APCI+ m/z 331 [MH]+.

Workup

  1. temperatureThe mixture was cooled in an ice-acetone bath
  2. concentrationThe reaction mixture was then concentrated in vacuo
  3. additionTriethylamine (7 ml) was added at 0° C.
  4. stirringthe mixture stirred at 0° C. for 30 minutes
  5. additionN,N-Dimethylformamide (10 ml) was added at 0° C.
  6. stirringstirred for 18 hours
  7. concentrationThe reaction mixture was concentrated in vacuo
  8. extractionextracted with ethyl acetate (2×150 ml)
  9. dry with materialdried over sodium sulphate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 95:5:0.5 by volume)

Sources & evidence

ORD record
ord-ac93e62d82e14be085da90027629df33
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

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