Chlorotrimethylsilane → Ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate

HRID 1168183Notes

Reaction equation

HRID 1168183 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[K+].[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.Cl[Si](C)(C)C.C1CCN2C(=NCCC2)CC1>CC#N.CCOC(C)=O.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](=[O:6])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]

Participants

8

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 27789252-Fluoro-5-iodobenzoic acidHCID 3446434Potassium ethyl malonate

Product 1

HCID 22397214Ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-fluoro-5-iodobenzoic acid (Prep. 1, 4.03 g) in 11 mL freshly distilled THF is added 1,1-carbonyldiimidazole (CDI) (2.96 g) in small portions. Vigorous gas evolution is observed. The reaction is stirred overnight. In a separate flask, ethyl malonate potassium salt (2.84 g) is suspended in 10 mL CH3CN. To this solution is added chlorotrimethylsilane (2.15 mL) and the reaction is stirred at room temperature overnight. The latter reaction is cooled to 0° C. and DBU (5.00 mL) is added dropwise. This reaction is stirred at 0° C. for 3 h. The solution of the CDI adduct is then cannulated over and the mixture is stirred at 0° C. for 2 h. Upon complete conversion to product as evidenced by TLC, the solution is quenched with water and 6N HCl (8 mL). The reaction is partitioned with diethyl ether. The organic layer is washed with 1N HCl and then brine, dried over Na2SO4, filtered, and concentrated to give a light orange oil. The oil is dissolved in EtOAc and adsorbed onto silica. Purification by chromatography (eluent 3% EtOAc/hexanes) affords the desired product as a colorless oil which crystallized upon standing (2.51 g, 49%). Physical characteristics are as follows: m.p. 54-56° C.; 1H NMR (300 MHz, CDCl3) δ12.67, 8.18, 7.70, 6.89, 5.54, 4.28, 1.35; IR (drift) 2984, 1627, 1558, 1476, 1422, 1390, 1358, 1292, 1262, 1221, 1201, 1071, 1028, 823, 807 cm−1; MS (EI) m/z 336 (M+), 336, 249, 122, 107, 94, 86, 84, 69, 68, 51; Anal. Calcd for C11H10FIO3: C, 39.31; H, 3.00; Found: C, 39.35; H, 2.92.

Workup

  1. stirringthe reaction is stirred at room temperature overnight
  2. customThe latter reaction
  3. stirringThis reaction is stirred at 0° C. for 3 h
  4. stirringis stirred at 0° C. for 2 h
  5. customthe solution is quenched with water and 6N HCl (8 mL)
  6. customThe reaction is partitioned with diethyl ether
  7. washThe organic layer is washed with 1N HCl
  8. dry with materialbrine, dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customto give a light orange oil
  12. customPurification by chromatography (eluent 3% EtOAc/hexanes)

Sources & evidence

ORD record
ord-cecb8ca35fef433d9473d7f84e718ec5
Source dataset
uspto-grants-2003_09
Patent number
US06624160B2

Reaction notes

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