Methyl iodide → HCID 66736922, compound

HRID 1640948Notes

Reaction equation

HRID 1640948 reaction equation
[H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:18])[C:5]=1[O:19][CH3:20].[CH:21]1([N:24]=[C:25]=[S:26])[CH2:23][CH2:22]1.[CH3:27]I>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:17])=[C:11]([CH2:27][S:26][CH:25]=[N:24][CH:21]2[CH2:23][CH2:22]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:6]([F:18])[C:5]=1[O:19][CH3:20]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 92463Cyclopropyl isothiocyanateHCID 16102689Ethyl 3-(4-bromo-2-fluoro-3-methoxyphenyl)-3-oxopropanoate

Product 1

HCID 66736922HCID 66736922, compoundYield 76.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

Sodium hydride (60% in mineral oil, 73.7 mg, 1.92 mmol) is added portionwise to a cooled (0° C.) solution containing 13 (569 mg, 1.78 mmol), cyclopropyl isothiocyanate (500 μL, 5.40 mmol), and dimethylformamide (5.0 mL). The resulting mixture was allowed to warm to room temperature with stirring overnight (18.5 h). Methyl iodide (700 μL, 11.22 mmol) is added to the resulting solution to give a precipitate within minutes. The mixture is stirred for an additional 24 h. The reaction mixture is quenched by addition of a saturated aqueous solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts are washed with brine (200 mL), dried over magnesium sulfate, and evaporated under reduced pressure to give the crude product. This material is purified by flash column chromatography (eluting with 10% v/v ethyl acetate in methylene chloride; Rf 0.59) to give 586.0 mg (76% yield) of 14 as a viscous yellow oil. 1H NMR (CDCl3): δ 0.86 (m, 2H, c-Pr CH2), 0.89 (t, JH-H=7.0 Hz, CO2CH2CH3), 0.98 (m, 2H, c-Pr CH2), 2.52 (s, 3H, S—CH3), 3.01 (m, 1H, c-Pr CH), 3.90 (q, JH-H=7.0 Hz, 2H, CO2CH2CH3), 3.94 (d, JH-F=1.5 Hz, 3H, OCH3), 6.97 (dd, JH-H=8.5 Hz, JH-F=6.5 Hz, 1H, aromatic H-6), 7.30 (dd, JH-H=8.5 Hz, JH-F=1.5 Hz, 1H, aromatic H-5), 11.91 (br, 1H, OH). 19F{1H} NMR (CDCl3): 8-130.4 (s). 13C{1H} NMR (CDCl3): δ 8.6 (c-Pr CH2), 13.5 (CO2CH2CH3), 18.1 (S—CH3), 28.5 (c-Pr CH), 60.3 (CO2CH2CH3), 61.4 (d, JC-F=5.0 Hz, OCH3), 104.2 (—C(OH)═C(CO2CH2CH3)—), 118.3 (d, JC-F=2.5 Hz, aromatic C-4), 123.4 (d, JC-F=3.5 Hz, aromatic C-6), 127.6 (d, JC-F=3.5 Hz, aromatic C-5), 131.9 (d, JC-F=14.5 Hz, aromatic C-1), 145.1 (d, JC-F=13.5 Hz, aromatic C-3), 152.6 (d, JC-F=253.0 Hz, C-2), 167.7 (CO2CH2CH3), 174.5 (—N═C(S—CH3)—), 185.5 (—C(OH)═C(CO2CH2CH3)—). LCMS m/z calcd for C17H1979BrFNO4S ([M]+) 431. Found 432 ([M+H]+). HRMS m/z calcd for C17H2079BrFNO4S 432.0280 ([M+H]+). Found 432.0276.

Workup

  1. temperatureto warm to room temperature
  2. customto give a precipitate within minutes
  3. stirringThe mixture is stirred for an additional 24 h
  4. customThe reaction mixture is quenched by addition of a saturated aqueous solution of ammonium chloride (50 mL)
  5. extractionextracted with ethyl acetate (3×100 mL)
  6. washThe combined organic extracts are washed with brine (200 mL)
  7. dry with materialdried over magnesium sulfate
  8. customevaporated under reduced pressure
  9. customto give the crude product
  10. customThis material is purified by flash column chromatography (
  11. washeluting with 10% v/v ethyl acetate in methylene chloride

Sources & evidence

ORD record
ord-14604138554d4dba81d667586600cce6
Source dataset
uspto-grants-2012_02
Patent number
US08114888B2

Reaction notes

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