Sodium Carbonate → 5-(Ethoxymethoxy)-2-(4-fluorophenyl)pyrimidine

HRID 2066632Notes

Reaction equation

HRID 2066632 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH3:28])=[CH:20][N:19]=1>C1(C)C=CC=CC=1.CCO.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:27]([O:26][CH2:25][O:24][C:21]1[CH:20]=[N:19][C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:23][CH:22]=1)[CH3:28]

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 2856454-Fluorophenylboronic acidHCID 866505392-Chloro-5-(ethoxymethoxy)pyrimidine

Product 1

HCID 669571525-(Ethoxymethoxy)-2-(4-fluorophenyl)pyrimidineYield 91.1%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 1140TolueneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
86 °C

Procedure

A stirred mixture of 4-fluorophenylboronic acid (282 mg, 2.02 mmol) and Pd(dppf)Cl2 (199 mg, 0.272 mmol) in toluene (14 mL) and EtOH (7 mL) was degassed for 10 min (vacuum pump) and then N2 was added. An aqueous solution of 2M Na2CO3 (3.3 mL, 6.6 mmol) was added by syringe and the stirred mixture was again degassed for 10 min, and then N2 was added, followed by chloropyrimidine 108 (260 mg, 1.38 mmol). The resulting mixture was stirred at 86° C. for 2.5 h, and then cooled, diluted with aqueous NaHCO3 (50 mL) and extracted with CH2Cl2 (5×50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% Et2O/petroleum ether firstly gave foreruns, and then further elution with 2% Et2O/petroleum ether gave 5-(ethoxymethoxy)-2-(4-fluorophenyl)pyrimidine (109) (312 mg, 91%) as a white solid: mp (petroleum ether) 42-44° C.; 1H NMR (CDCl3) δ 8.58 (s, 2H), 8.36 (ddt, J=9.0, 5.6, 2.5 Hz, 2H), 7.14 (tt, J=8.8, 2.5 Hz, 2H), 5.30 (s, 2H), 3.77 (q. J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H); HRESIMS calcd for C13H13FN2O2 m/z [M+H]+ 249.1034. found 249.1039.

Workup

  1. customwas degassed for 10 min (vacuum pump)
  2. additionN2 was added
  3. customthe stirred mixture was again degassed for 10 min
  4. additionN2 was added
  5. temperaturecooled
  6. extractionextracted with CH2Cl2 (5×50 mL)
  7. customThe extracts were evaporated to dryness
  8. customthe residue was chromatographed on silica gel
  9. washElution with 0-2% Et2O/petroleum ether firstly gave foreruns
  10. washfurther elution with 2% Et2O/petroleum ether

Sources & evidence

ORD record
ord-b37c2a10793549f29163c2b069012682
Source dataset
uspto-grants-2012_10
Patent number
US08293734B2

Reaction notes

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