2,6-Lutidine → Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate

HRID 2402153Notes

Reaction equation

HRID 2402153 reaction equation
[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=C)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].I([O-])(=O)(=O)=[O:32].[Na+].N1C(C)=CC=CC=1C>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[O:32])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]

Participants

8

Reactant 3

HCID 79372,6-LutidineHCID 23667635Sodium periodateHCID 68006701Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate

Product 1

HCID 86667483Ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylateYield 43.5%

Reagents, catalysts & solvents 4

HCID 962WaterCatalystHCID 30318Osmium TetroxideCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a suspension of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (247 mg, 0.531 mmol) in 1,4-dioxane (6.00 mL) and water (2.00 mL) was added sodium metaperiodate (454 mg, 2.12 mmol), 2,6-lutidine (246 uL, 2.12 mmol), and 4% osmium tetroxide in water (4:96, osmium tetraoxide:water, 64.9 uL, 0.0106 mmol). The reaction was vigorously stirred at rt for 5 hrs. The mixture was filtered over a celite pad and the filtered solid was rinsed with EtOAc. The filtrate was washed with NaHCO3(aq) saturated solution and the aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 1N HCl soln and brine, dried, and concentrated. Purification on a silica gel column (gradient elution 5-50% EtOAc/hexanes) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a yellow syrup (108 mg, 43.5% yield). 1H NMR (400 MHz, CDCl3) δ 9.84-9.73 (d, J=1.3 Hz, 1H), 7.48-7.42 (d, J=2.1 Hz, 1H), 7.42-7.32 (d, J=8.4 Hz, 1H), 7.30-7.18 (m, 1H), 6.06-5.94 (t, J=−7.7 Hz, 1H), 4.38-4.26 (q, J=7.1 Hz, 2H), 3.86-3.77 (t, J=4.9 Hz, 4H), 3.62-3.51 (dd, J=5.7, 4.0 Hz, 4H), 3.50-3.42 (m, 2H), 1.41-1.29 (m, 3H).

Workup

  1. filtrationThe mixture was filtered over a celite pad
  2. washthe filtered solid was rinsed with EtOAc
  3. washThe filtrate was washed with NaHCO3(aq) saturated solution
  4. extractionthe aqueous layer was extracted with EtOAc (×2)
  5. washThe combined organic layer was washed with 1N HCl soln and brine
  6. customdried
  7. concentrationconcentrated
  8. customPurification
  9. washon a silica gel column (gradient elution 5-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-c52d459ee91d4005b6093cd50e84af6b
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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