Chlorotrimethylsilane → 1-Chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene

HRID 332930Notes

Reaction equation

HRID 332930 reaction equation
BrCCBr.Cl[Si](C)(C)C.[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49]>C1COCC1.[Zn].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]>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[O:48][CH3:49])[C:12]=1[F:19]

Participants

9

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 11776TriphenylphosphineHCID 872661-Bromo-2,4-dimethoxybenzeneHCID 5228271-(Bromomethyl)-3-chloro-2-fluorobenzene

Product 1

HCID 714875021-Chloro-3-(2,4-dimethoxybenzyl)-2-fluorobenzene

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
60 °C

Procedure

THF (5 volumes) and zinc dust (2.4 eq) were charged to a round bottom flask under nitrogen. The slurry was heated to 60° C. and held for 15 min. 1,2-Dibromoethane (0.2 eq) was added and the mixture agitated at 60° C. for 30 min. The mixture was cooled to ambient temperature before 0.4 eq. chlorotrimethylsilane was added. 3-Chloro-2-fluorobenzylbromide (2.0 eq) dissolved in THF was added over 2 h at 0° C. Agitation was stopped and the mixture allowed to settle overnight to give 7 as a solution in THF. Next, 0.16 eq Pd2dba3 and 0.35 eq. triphenylphosphine were charged to a separate flask under argon. THF (10 volumes) and 1-bromo-2,4-dimethoxybenzene were added followed by the solution of compound 7 prepared above. The mixture was heated to 65° C. and agitated overnight. The mixture was cooled to room temperature and quenched with aqueous NH4OH. The organic phase was purified by column chromatography to yield compound 5: 1H NMR (400 MHz, CDCl3): δ 7.33 (td, 1H, J=7, 2 Hz), 7.07-6.99 (m, 2H), 6.91 (d, 1H, J=8 Hz), 6.49 (d, 1H, J=8 Hz), 6.40 (dd, 1H, J=8, 2 Hz), 3.80 (s, 2H), 3.68 (s, 3H), 3.67 (s, 3H).

Workup

  1. additionwas added
  2. additionwas added over 2 h at 0° C
  3. waitto settle overnight
  4. customprepared above
  5. temperatureThe mixture was heated to 65° C.
  6. stirringagitated overnight
  7. temperatureThe mixture was cooled to room temperature
  8. customquenched with aqueous NH4OH
  9. customThe organic phase was purified by column chromatography

Sources & evidence

ORD record
ord-0c895ce13f0d4423b45dda11eecc484c
Source dataset
uspto-grants-2014_11
Patent number
US08877931B2

Reaction notes

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