tert-Butyl acetate → (7-Chloro-2-methyl-quinolin-8-yl)-acetic acid tert-butyl ester

HRID 505225Notes

Reaction equation

HRID 505225 reaction equation
C([Li])CCC.C[Si](C)(C)[N-][Si](C)(C)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[C:43]([O:47][C:48](=[O:50])[CH3:49])([CH3:46])([CH3:45])[CH3:44].[Cl:51][C:52]1[C:61](OS(C(F)(F)F)(=O)=O)=[C:60]2[C:55]([CH:56]=[CH:57][C:58]([CH3:70])=[N:59]2)=[CH:54][CH:53]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:43]([O:47][C:48](=[O:50])[CH2:49][C:61]1[C:52]([Cl:51])=[CH:53][CH:54]=[C:55]2[C:60]=1[N:59]=[C:58]([CH3:70])[CH:57]=[CH:56]2)([CH3:46])([CH3:45])[CH3:44]

Participants

8

Reactant 5

HCID 10908tert-Butyl acetateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 3280088Npc316347HCID 86625791Trifluoro-methanesulfonic acid 7-chloro-2-methyl-quinolin-8-yl esterHCID 178418339Butyllithium

Product 1

HCID 66881451(7-Chloro-2-methyl-quinolin-8-yl)-acetic acid tert-butyl esterYield 40%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
-78 °C

Procedure

n-Butyl lithium (1.6 M in hexane, 5.3 ml, 8.52 mmol, 1.5 equiv) was added at −78° C. under an atmosphere of argon to a degassed solution of hexamethyl disilazide (1.38 g, 8.52 mmol, 1.5 equiv) in toluene (16 ml). After stirring at −78° C. for 15 minutes and at room temperature for 15 minutes, Pd2(dba)3 (156 mg, 0.17 mmol, 0.03 equiv) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (141 mg, 0.36 mmol, 0.063 equiv) were added. After stirring at room temperature for 10 minutes, the reaction mixture was cooled to −10° C. and treated dropwise with acetic acid tert-butyl ester (858 mg, 7.38 mmol, 1.3 equiv). After stirring for 10 minutes at −10° C., trifluoro-methanesulfonic acid 7-chloro-2-methyl-quinolin-8-yl ester (1.85 g, 5.68 mmol) was added in one portion, and the cooling bath was removed. The temperature of the reaction mixture rose to 29° C. within the next 30 minutes. After 40 minutes, TLC analysis indicated formation of unwanted side products (e.g. 4-(7-chloro-2-methyl-quinolin-8-yl)-3-oxo-butyric acid tert-butyl ester). The reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of toluene/EtOAc 100:0 to 95:5) to afford the title compound (662 mg, 40%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.98 (d, J=12.8 Hz, 1H), 7.63 (d, J=12.8 Hz, 1H), 7.47 (d, J=12.8 Hz, 1H), 7.26 (d, J=12.8 Hz, 1H), 4.43 (s, 2H), 2.72 (s, 3H), 1.47 (s, 9H). MS (ES+): 292.2 (M+H)+.

Workup

  1. stirringAfter stirring at room temperature for 10 minutes
  2. temperaturethe reaction mixture was cooled to −10° C.
  3. stirringAfter stirring for 10 minutes at −10° C.
  4. customthe cooling bath was removed
  5. customrose to 29° C. within the next 30 minutes
  6. waitAfter 40 minutes
  7. additionThe reaction mixture was diluted with water
  8. filtrationfiltered
  9. extractionextracted with EtOAc
  10. washThe combined organic layers were washed with brine
  11. dry with materialdried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customThe residue was purified via flash chromatography (gradient of toluene/EtOAc 100:0 to 95:5)

Sources & evidence

ORD record
ord-f523124c491a4a1b835df5c29d417852
Source dataset
uspto-grants-2010_08
Patent number
US07781438B2

Reaction notes

Loading…