N-Methoxy-N-methylacetamide → 1-(2-Chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanone

HRID 411243Notes

Reaction equation

HRID 411243 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[Cl:7].C([Li])CCC.CON(C)[C:23](=[O:25])[CH3:24]>C(OCC)C>[Cl:7][C:6]1[S:5][C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:3][C:2]=1[C:23](=[O:25])[CH3:24]

Participants

5

Reactant 3

HCID 537505N-Methoxy-N-methylacetamideHCID 223972434-((4-Bromo-5-chlorothiophen-2-yl)methyl)morpholineHCID 178418339Butyllithium

Product 1

HCID 223972051-(2-Chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanoneYield 37%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-75 °C

Procedure

4-((4-Bromo-5-chloro-2-thienyl)methyl)morpholine (Preparation 62, 7.65 g) is dissolved in diethyl ether (75 mL) and is cooled to −75° C. A solution of n-butyllithium (2.5 M in hexane, 11.0 mL) is added via addition funnel, maintaining the temperature below 68° C. The reaction is stirred for 15 minutes at −70° C. and allowed to warm to 0° C. A solution of N-methoxy-N-methylacetamide (3.09 g) in ether (5 mL) is added via addition funnel, maintaining the temperature below 5° C. The reaction is stirred at 0° C. for 1 h and allowed to warm to rt. The reaction is quenched with saturated aq. NH4Cl solution (50 mL) and made basic with sat. aq. NaHCO3. The mixture is extracted with ethyl acetate (3×125 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is chromatographed, eluting with 25% ethyl acetate/heptane to afford 2.42 g (37%) of the title compound. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ 7.33, 3.64, 3.58, 2.51; IR (liq.) 2854, 2809, 1673, 1456, 1372, 1351, 1328, 1243, 1212, 1165, 1118, 1034, 1008, 867, 618 cm−1; HRMS (FAB) m/z 260.0506 (C11H14ClNO2S+H). Anal. Found: C, 50.77; H, 5.51; N, 5.35; Cl, 13.24; S, 12.00.

Workup

  1. temperaturemaintaining the temperature below 68° C
  2. temperatureto warm to 0° C
  3. temperaturemaintaining the temperature below 5° C
  4. stirringThe reaction is stirred at 0° C. for 1 h
  5. temperatureto warm to rt
  6. customThe reaction is quenched with saturated aq. NH4Cl solution (50 mL)
  7. extractionThe mixture is extracted with ethyl acetate (3×125 mL)
  8. washThe combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL)
  9. extractionThe combined aqueous washes are back-extracted with ethyl acetate (100 mL)
  10. dry with materialdried (Na2SO4)
  11. concentrationconcentrated in vacuo to a yellow oil
  12. customThe crude product is chromatographed
  13. washeluting with 25% ethyl acetate/heptane

Sources & evidence

ORD record
ord-8d1c57c73c0a4ae19996b74d8d21df59
Source dataset
uspto-grants-2003_05
Patent number
US06559145B2

Reaction notes

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