1-Ethynyl-4-fluorobenzene → HCID 90402679, compound

HRID 1854723Notes

Reaction equation

HRID 1854723 reaction equation
[C:1]([O:4][C:5]1[C:10](I)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15]>C1COCC1.[Cu]I>[C:1]([O:4][C:5]1[C:10]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:9][C:8]([Br:12])=[C:7]([Cl:13])[N:6]=1)(=[O:3])[CH3:2]

Participants

5

Reactant 2

HCID 5226271-Ethynyl-4-fluorobenzeneHCID 90402444HCID 90402444, compound

Product 1

HCID 90402679HCID 90402679, compoundYield 82.3%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

5-bromo-6-chloro-3-iodopyridin-2-yl acetate (14.5 g, 38.5 mmol) was dissolved in THF (50 mL) and cooled to 0° C. TEA (2.5 mL), Copper(I)Iodide (0.514 g, 2.70 mmol), and bistriphenylphosphine palladiumdichloride (0.270 g, 0.385 mmol) were added to the reaction mixture. The mixture was degassed and charged with N2 (3×). Next, 1-ethynyl-4-fluorobenzene (5.55 g, 46.2 mmol) was added drop wise over the course of 1 h at 0° C. The reaction mixture was then allowed to slowly warm to rt and continue to stir for 18 h. LCMS and TLC show the reaction to be incomplete. An additional 2.5 mL of TEA was added. The mixture was then allowed to stir at rt over a long weekend (80 h). At this point, LCMS and TLC show no remaining starting material. The reaction mixture was concentrated to a dry solid. This solid was then taken up in DCM (50 mL) and washed with sat NH4Cl. The aq layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, filtered and concentrated to >15 g of a brown solid. This solid was dissolved in DCM, adsorbed onto Celite and then flashed on silica gel eluting with a 10-100% DCM in hexanes gradient over 15 column volumes to give 5-bromo-6-chloro-3-((4-fluorophenyl)ethynyl)pyridin-2-yl acetate (11.7 g, 31.7 mmol, 82% yield) as a tan solid. LCMS: m/e 369 (M+H)+ LCMS retention time: 3.74 min. (Column: Phenomenex-Luna 50×2.0 mm 3u. Solvent A=90% Water: 10% Methanol: 0.1% TFA. Solvent B=10% Water: 90% Methanol: 0.1% TFA. Start % B=0. Final % B=100. Gradient Time=4 min. Flow Rate=0.8 mL/min.). 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 1H), 7.48 (dd, J=8.7 Hz, 2H), 7.09 (dd, J=8.7 Hz, 2H), 2.39 (s, 3H).

Workup

  1. customThe mixture was degassed
  2. additioncharged with N2 (3×)
  3. temperatureto slowly warm to rt
  4. customthe reaction
  5. stirringto stir at rt over a long weekend (80 h)
  6. concentrationThe reaction mixture was concentrated to a dry solid
  7. washwashed
  8. extractionThe aq layer was extracted with DCM (2×20 mL)
  9. washThe combined organic extracts were washed with water, brine
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated to >15 g of a brown solid
  13. dissolutionThis solid was dissolved in DCM

Sources & evidence

ORD record
ord-4325ae348f4247af94d32bae7b73827b
Source dataset
uspto-grants-2015_02
Patent number
US08962651B2

Reaction notes

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