Trifluoroacetic acid → 6-Fluoro-3-methylquinoline

HRID 2281130Notes

Reaction equation

HRID 2281130 reaction equation
C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(C)(C)C.[C:16]([Li])(C)([CH3:18])[CH3:17].CCO/C=C(/C=O)\C.FC(F)(F)C(O)=O.[OH-].[Na+]>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:16]([CH3:18])=[CH:17]2

Participants

6

Reactant 5

HCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 30848683-Ethoxy-2-methylacrylaldehydeHCID 4935450Tert-butyl 4-fluorophenylcarbamateHCID 178418306HCID 178418306, compound

Product 1

HCID 157236166-Fluoro-3-methylquinolineYield 3%

Conditions

Temperature
-20 °C

Procedure

(4-Fluoro-phenyl)-carbamic acid tert-butyl ester (2.11 g, 10.0 mmol, ABCR, Karlsruhe, Germany) was added to a round bottom and purged with nitrogen. Anhydrous tetrhydrofuran (200 mL) was added to dissolve the solids and the flask placed in a dry ice/acetone bath (internal temperature −74° C. uncorrected). tert-Butyl lithium (1.7 M in pentane, 14.2 mL, 24.0 mmol) was added over 5 min causing a yellow color to develop. After the addition was complete the reaction was stirred in a −20° C. bath for 1 h. At this point, 3-ethoxymethacrolein (1.43 mL, 12.0 mmol) was added dropwise over 5 min, keeping the temperature below −19° C. The reaction was stirred at −20° C. for 2 h before slowly adding trifluoroacetic acid (14 mL) over 5 min. The red solution was stirred at room temperature for 16 h before bring to pH 12 with 1 N NaOH. This was extracted twice with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyle acetate/heptanes) gave impure desired material. This was extracted into three portions of 1 N HCl, the combined aqueous layers were brought to pH 12 with 6 N NaOH, and then extracted into two portions of ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo to give 6-fluoro-3-methyl-quinoline (48.0 mg) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1 H) 8.07 (dd, J=9.1, 5.4 Hz, 1 H) 7.88 (s, 1 H) 7.33-7.46 (m, 2 H) 2.53 (s, 3 H); MS (M+1): 162.1.

Workup

  1. custompurged with nitrogen
  2. additionAnhydrous tetrhydrofuran (200 mL) was added
  3. dissolutionto dissolve the solids
  4. customthe flask placed in a dry ice/acetone bath
  5. custom(internal temperature −74° C. uncorrected)
  6. additionAfter the addition
  7. customthe temperature below −19° C
  8. stirringThe red solution was stirred at room temperature for 16 h
  9. extractionThis was extracted twice with ethyl acetate
  10. dry with materialthe combined organics dried over MgSO4
  11. customPurification by silica gel flash chromatography (ethyle acetate/heptanes)
  12. customgave impure desired material
  13. extractionThis was extracted into three portions of 1 N HCl
  14. extractionextracted into two portions of ethyl acetate
  15. dry with materialThe combined organics were dried over MgSO4
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-560cd9bdfe314aceadb5050779c01d63
Source dataset
uspto-grants-2015_09
Patent number
US09139538B2

Reaction notes

Loading…