Chlorotrimethylsilane → Methyl 4-(thiazol-2-ylmethyl)benzoate

HRID 1039954Notes

Reaction equation

HRID 1039954 reaction equation
BrCCBr.[Si](Cl)(C)(C)C.Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.Br[Zn]CC1C=CC(C(OC)=O)=CC=1.Br[C:36]1[S:37][CH:38]=[CH:39][N:40]=1>C1COCC1.[NH4+].[Cl-].O.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[S:37]1[CH:38]=[CH:39][N:40]=[C:36]1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1

Participants

11

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 764302-BromothiazoleHCID 256687Methyl 4-(bromomethyl)benzoateHCID 178497887HCID 178497887, compound2×

Product 1

HCID 67249380Methyl 4-(thiazol-2-ylmethyl)benzoateYield 99%

Reagents, catalysts & solvents 5

HCID 23994ZincCatalyst3×HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent5×HCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
70 °C

Procedure

Zinc dust, <10 micron (2.227 g, 34.1 mmol) was suspended in THF (5 ml), and 1,2-dibromoethane (0.090 ml, 1.048 mmol) was added. The mixture was stirred for 10 min at 70° C. It was then cooled to room temperature, and TMS-Cl (0.100 ml, 0.786 mmol) was added. After 30 min at room temperature, the activated zinc was cooled to 0° C., and methyl 4-(bromomethyl)benzoate) (6.00 g, 26.2 mmol) in THF (20 ml) was added drop-wise over 75 min (˜2 mL every ˜5-7 min). After stirring for another 1 h at 0° C., another portion of THF (25 ml) was added to dilute to ˜0.5 M. The gray suspension was allowed to stand so the remaining zinc solid would settle, and the supernatant was used as bromo[4-(methoxycarbonyl)benzyl]zinc (0.5 M in THF). Palladium(II) acetate (103 mg, 0.457 mmol), and 2-dicylochexylphosphino-2′,6′-dimethoxy-1′,1′,biphenyl (375 mg, 0.915 mmol) were combined in a flask, sealed, and flushed with nitrogen (2×). Degassed THF (15 ml), 2-bromothiazole (0.408 ml, 4.57 mmol), and the freshly prepared 0.5 M bromo[4-(methoxycarbonyl)benzyl]zinc in THF (27.4 ml, 13.72 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NH4Cl and water before being extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (0-50% EtOAc/hexanes) afforded methyl 4-(1,3-thiazol-2-ylmethyl)benzoate (1.06 g, 4.54 mmol, 99%) as a yellow oil that crystallized upon standing. MS ESI: [M+H]+ m/z 234.0.

Workup

  1. temperatureIt was then cooled to room temperature
  2. waitAfter 30 min at room temperature
  3. stirringAfter stirring for another 1 h at 0° C.
  4. additionto dilute to ˜0.5 M
  5. customsealed
  6. customflushed with nitrogen (2×)
  7. stirringthe reaction was stirred at room temperature overnight
  8. extractionbefore being extracted with EtOAc (2×)
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d6982515218a4227b1f8a70523302059
Source dataset
uspto-grants-2013_10
Patent number
US08551984B2

Reaction notes

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