Tributyltin Chloride → 3-(2-Chloropyrimidin-4-yl)-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-alpha]pyridine

HRID 1765102Notes

Reaction equation

HRID 1765102 reaction equation
C([Mg]Cl)(C)C.Br[C:7]1[N:11]2[CH:12]=[CH:13][C:14]([C:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:22][CH3:23])([CH3:19])[CH3:18])=[C:15]([F:16])[C:10]2=[N:9][CH:8]=1.C([Sn](Cl)(CCCC)CCCC)CCC.[Cl:42][C:43]1[N:48]=[C:47](Cl)[CH:46]=[CH:45][N:44]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O>[Cl:42][C:43]1[N:48]=[C:47]([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:17]([O:20][Si:21]([CH2:26][CH3:27])([CH2:22][CH3:23])[CH2:24][CH3:25])([CH3:18])[CH3:19])=[C:15]([F:16])[C:10]3=[N:9][CH:8]=2)[CH:46]=[CH:45][N:44]=1

Participants

9

Reactant 4

HCID 15096Tributyltin ChlorideHCID 775312,4-DichloropyrimidineHCID 695489923-Bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-alpha]pyridineHCID 178418918HCID 178418918, compound

Product 1

HCID 878862453-(2-Chloropyrimidin-4-yl)-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-alpha]pyridine

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

Isopropylmagnesium chloride (2.0M in THF; 5.7 ml, 11.4 mmol) was added dropwise to a stirred, cold (−78° C.) solution of 3-bromo-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine (4.0 g, 10.3 mmol) in THF (80 ml). After 10 min, tri-n-butyltin chloride (3.22 ml, 11.9 mmol) was added in a single portion and the mixture was stirred for 30 min, then warmed to ambient temperature. 2,4-Dichloropyrimidine (2.31 g, 15.5 mmol) was added and the mixture degassed by bubbling through N2. Tetrakis(triphenylphosphine)palladium(0) (1.19 g, 1.03 mmol) and copper(I) iodide (19.7 mg, 0.1 mmol) were then added in single portions and the reaction was heated to reflux for 18 h. On cooling, water (80 ml) was added and the phases separated. The aqueous was extracted with EtOAc (40 ml) and the combined organics washed with brine (40 ml), dried over MgSO4, filtered and concentrated in vacuo. Purified by column chromatography (silica, 0 to 5% MeOH in CH2Cl2) and the semi-pure product washed with 1:2 Et2O/isohexane to afford 3-(2-chloropyrimidin-4-yl)-8-fluoro-7-[2-(triethylsilyloxy)prop-2-yl]imidazo[1,2-α]pyridine as a white amorphous solid (3.4 g): m/z (ES+) 421 (100%, [MH]+) and 423 (30).

Workup

  1. customthe mixture degassed
  2. customby bubbling through N2
  3. temperaturethe reaction was heated
  4. temperatureto reflux for 18 h
  5. temperatureOn cooling
  6. customthe phases separated
  7. extractionThe aqueous was extracted with EtOAc (40 ml)
  8. washthe combined organics washed with brine (40 ml)
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customPurified by column chromatography (silica, 0 to 5% MeOH in CH2Cl2)
  13. washthe semi-pure product washed with 1:2 Et2O/isohexane

Sources & evidence

ORD record
ord-7bb3536f5f6f4feea1f193a200f0b481
Source dataset
uspto-grants-2007_06
Patent number
US07226926B2

Reaction notes

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