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9th December 2016 @ 19:30

O=C(C1=NC(Cl)=CN=C1)C(F)(F)F

 

Reference

Holsinger, L.J., Compounds that Inhibit Protease Cathepsins and HCV Replication. U.S. Patent 2008080785, April 30, 2009.

 UNSUCCESSFUL
 

Substance

Amount

Mol. wt.

mmols

Equiv.

Starting Material

1 g

172.57

5.79

1

trimethylsilyltrifluoro-methane

0.70 g

142.2

4.92

0.85

caesium fluoride

0.880

151.9

5.79

1

tetra-butylammoniun fluoride (1M in THF)

7.25 mL

261.46

7.25

1.25

Concentrated Acetic Acid (17.4 M)

2.8 mL

 

49.2

8.5

Product

 

1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one

1.033 g (Theoretical)

 

0.1127 mg

(Actual)

209.98

4.92 (Theoretical)

 

0.54

(Actual)

0.85 (Theoretical)

 

11% Yield

(Actual)

 

Procedure:

(11/30/16)

 
  1. Dissolved starting material in dimethoxy ethane (15 mL).

  2. Dried CsF (0.88g) under vacuum while heating with a heat gun.

  3. Add trimethylsilyltrifluoro-methane (0.82 g) and CsF (0.880 g) to the starting material solution.

  4. Stirred at 4 degrees celsius for 36 hours.
    (12/2/16)

  5. A TLC was taken to see if the reaction was complete.

  6. The reaction was then concentrated at room temperature in high vac to a brown oil.



    (12/7/16)

  7. The concentrated product was then dissolved in 10 mL of THF, 2.8 mL acetic acid, and treated with 7.25 mL of tetrabutylammonium fluoride.

  8. Reaction was aged for 3 hours and then stopped by diluting the reaction with ethyl acetate (20 mL). A TLC was taken after 3 hours but no change was observed between the starting material before the workup and the product after the workup.

  9. The product was then gravity filtered to remove excess CsF.

  10. Product was washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions).

  11. Washed with brine (100 mL).

  12. Dried over anhydrous magnesium sulfate, then filtered.

  13. Concentrated in vacuo.

1;1 Ethyl Acetate : Hexanes; S → Starting Material, C→ Co-Spot, P → Product
(12/8/16)

  1. Triturated brown oil product in a minimal amount of dichloromethane and hexanes to yield a brown solid.

    1. Yield: 0.1127 g (11%)

 

Analysis: In order to determine the identity of the product, GCMS and NMR were run.

 

GCMS:

 
[Untitled].pdf

The Peak at 207 m/z is the same that was observed last attempt. The mass of the expected product is 209, thus this data suggests that the synthesis was not successful.

 

NMR:

Carbon:
VRBP_TheBurnsFinal_CARBON_cdcl3_01.pdf
 
Proton
VRBP_TheBurnsFinal_PROTON_cdcl3_01.pdf

Both Carbon and PRoton NMR do not match any the expected spectra for the desired product, which further suggests that the synthesis was not successful.

 

Conclusions:

 

Decreasing the temperature of the reaction and decreasing the molar equivalents of the reactants did not improve the outcome of the reaction. Looking back at the previous group that worked on this project, their data suggests that they too were not successful in making this compound. We would suggest that future attempts to synthesize “The Burns” take another synthesis route. One possible synthesis is proposed below:

 

other thing.jpg

 

The reference for this reaction didn’t perform this reaction exactly; however, it might still work. Another option is to come up with a complete new total synthesis for “The Burns” compound.

 
Attached Files
[Untitled].pdf
VRBP_TheBurnsFinal_PROTON_cdcl3_01.pdf
VRBP_TheBurnsFinal_CARBON_cdcl3_01.pdf