Haverford Superlab: Synthesizing \"The Burns\"

1. Dissolved starting material in dimethoxy ethane (10 mL). 
2. Added trimethylsilyltrifluoro-methane (0.70 mL) and caesium fluoride (0.051 g). 
3. Stirred at room temperature overnight. Solution turned a dark yellow, then brown color. 
4. Concentrated mixture under reduced pressure, resulting in a dark brown oil. 
   
   Step 3 brown oil.jpg
    
5. Dissolved resulting residue in THF (4.0 mL) and acetic acid (2.0 mL) 
6. Added tertbutylammonium fluoride (0.867 g) 
7. Allowed reaction to stir overnight. 
8. Diluted reaction with ethyl acetate (50 mL) 
9. Washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions). 
10. Washed with brine (100 mL) 
11. Dried over anhydrous magnesium sulfate, then filtered. 
12. Removed solvent under reduced pressure. 
13. Triturated with a 1:1 dichloromethane/hexanes solution (50 mL), causing a dark brown semi-solid to precipitate from solution. Results were not consistent with literature precedent.  
14. Removed solvent under reduced pressure, concentrating product back into a dark brown oil. 
    
    Dark brown oil re-rotovap.jpg
15. Crude product (dark brown oil) was tested via TLC.
    Left = SM, Center = cospot, Right = product
    
    TLC Crude Product 3.jpg
    
    1:1 EtOAc:Hexanes solvent system; silica gel plate; UV visualization
    Rf(bottom) = 0.25, Rf(middle) = 0.42, Rf(top) = 0.50
16. Purified solution using Biotage Isolera. Fractions 2, 3, 6 and 7 were shown to most likely contain the purified product.
    
    Step 3 Biotage Screen.JPG
17. Fractions were analyzed using TLC, GCMS, and NMR. Analysis of the results showed that fractions 6 and 7 contained the most pure sample of product 3, 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one.
18. Fractions 6 and 7 were combined and solvents removed in vacuo in preparation for step 4. 

Conclusions and Next Steps 

     From our TLC, GCMS, and NMR data, we have concluded that we produced some of our desired product, 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one. TLC of the crude product indicated an incomplete reaction as some UV-visualizable spots characteristic of the starting material were present in the product. However, after submitting the crude product to the Biotage Isolera, it appeared that we acheived some separation upon TLC and GCMS analysis. Although Fraction 2 appeared to contain some impurity in the TLC, fractions 3, 6, and 7 appeared to be fairly pure (with 6 and 7 containing the same product). We combined fractions 6 and 7, then submitted the 3 samples to GCMS. We found the combined fractions 6 and 7 appeared to be out desired product as we observed the M+ of m/z 209.98, which is characteristic of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one. However, upon analysis by NMR, we found that our product also likely contained the more reduced version of the product, 2-(6-chloropyrazin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol. This is evidenced by by the m/z 279.9, 281.9 in GCMS, as well as the peaks at 8.07 and 5.73 ppm in the 1HNMR. 

2-(6-chloropyrazin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Image courtesy of Chase Smith via Github)

In any repeat trials, shortening the reaction, running it at 0 deg. C, and/or reducing the amount of trimethylsilyltrifluoro-methane to 1 equivalent, may help to increase the yield of our desired product (advice courtesy of Chase Smith via Github).

     Because we produced primarily the desired product, we continued on with step 4 in which we will perform a reductive amination in an attempt to produce N-benzyl-1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-amine. However, for future trials, it may be more effective to perform another separation using Biotage Isolera in order to achieve a more pure product.  

1. Dissolved 2-(6-chloropyrazin-2(1I)-ylidene) malnonitrile (0.92 g, 5.15 mmol) in MeOH (54.2 mL).

2. Added Li2CO3 (0.571 g, 7.72 mmol) to this solution.

3. Stirred mixture for 30 min.

4. Added magnesium monoperoxyphthalate hexahydrate (1.911 g, 3.86 mmol) in small portions at 0 deg. C.

5. Allowed mixture to stir overnight in ice bath. 

6. The solution was dry filtrated in vacuo, resulting in a dark yellow residue. (9/13/2016)

   Step 2 yellow residue.jpg

7. Residue was partitioned between H2O (21 mL) and CHCl3 (21 mL).

8. Dried organic phase over MgSO4, and filtered through a short plug of silica.

9. Removed all volatiles in vacuo.

10. Product was a pale yellow oil that crystallized upon standing (0.60 g, 3.48 mmol, 67% yield). 

    Product 2.jpg

This procedure was repeated on 9/15/16 with the second batch of starting material, with amounts adjusted for 0.75 grams of starting material. 0.29 g (39.9 % yield) of product was collected.

• SM visualized by UV, not visualized by KMnO₄ or ninhydrin
• Product not visualized by UV, KMnO₄, or ninhydrin
• SM spots travelled too far up plate

Solvent system attempt #2: 1:2 EtOAc:Hex

• Same results as solvent system attempt #1

Attempted to redissolve product in methanol --> dissolved much more successfully

Solvent system attempt #4: 1:4 EtOAc:Hex

• SM visualized by UV, not visualized by KMnO4 or ninhydrin
• Product not visualized by any methods
  • Shows up as yellow-orange spot near bottom of plate (at starting point)

Solvent system attempt #5: 10% methanol in EtOAc

• SM and product visualized by UV
• Potentially trace amounts of SM in product

10% methanol in EtOAc solvent system, silica gel plate, UV visualization

Left = SM, Center = cospot, Right = product

Rf(SM) = 0.763, Rf(Prod)= 0.289