Reaction #531875

Reaction equation

Methyl-3,5-dichlorosalicylate

isopropyl magnesium chloride

→

ketone

1-(3,5-dichloro-2-hydroxyphenyl)-2-methylpropan-1-one

Solvents

THF

THF

Conditions

Workup

1. 1
   Temperaturewarmed to 25° C.
2. 2
   workup.STIRRINGstirred for 4 h
3. 3
   OtherThe excess reagent was quenched by addition of satd NH4Cl (10 mL)
4. 4
   workup.ADDITIONThe mixture was diluted with EtOAc (50 mL)
5. 5
   workup.ADDITIONthe pH was adjusted to ˜1 by addition of 1 M HCl
6. 6
   WashThe organic phase was washed with satd NaCl solution (20 mL)
7. 7
   Dryingdried (Na2SO4)
8. 8
   Otherevaporated
9. 9
   OtherThe residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile

Procedure

Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232.

Source