Dimethylformamide → Ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate

HRID 2401855Notes

Reaction equation

HRID 2401855 reaction equation
Cl[Si](C)(C)C.BrCCBr.CN(C)C=O.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:26]2[N:27]=[C:28]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[S:29][C:30]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:17][C:16]=1[F:15]

Participants

8

Reactant 5

HCID 6228Dimethylformamide2×HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 27831364-(Bromomethyl)-1-chloro-2-fluorobenzeneHCID 66749604Ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate

Product 1

HCID 66749173Ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylateYield 68.2%

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 178418851HCID 178418851, compoundCatalyst

Procedure

In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%).

Workup

  1. customIn a 50 ml flame-dried round bottom flask
  2. stirringthe resulting suspension was stirred overnight at room temperature
  3. temperaturewas heated
  4. stirringwith stirring at 60° C. for 60 min
  5. customReaction
  6. customwas quenched with saturated ammonium chloride
  7. customtransferred to a separatory funnel
  8. additioncontaining water (10 mL) and EtOAc (40 mL)
  9. customThe layers were separated
  10. extractionthe aqueous layer was extracted 2×30 mL with EtOAc
  11. washThe combined organic layers were washed 1× brine
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. dissolutionThe resulting residue was dissolved in DCM
  16. custompurified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-8252a2a5f2314943b2befbc70b350ab0
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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