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18th October 2016 @ 22:17


4 October 2016

Step 4 Scheme.jpg

Baxter, E. W.; Reitz, A. B. Organic Reactions 2002, 1–714. 
Data Table



Mol. wt.




70 mg




Benzylamine (Phenylmethylamine, 1-Phenylmethanamine)

35.63 mg, .036 mL




TiCl4 (1M in Chloroform)

0.167 mL x2





62.685 mg




Crude product

0.10 g (theoretical)

0.020 g (actual)




1 (theoretical)

0.2 (actual)


  1. Combine benzylamine and starting material in 10 mL chloroform (under argon in dried flask).

  2. Add titanium(IV) tetrachloride via syringe.

  3. Stir rxn mixture for 18 hours. (10/4/16) Turned a cloudy pale orange color. 

  4. Dissolve sodium cyanoborohydride in 3 mL MeOH, and add to mixture. Stir for 15 minutes.

  5. Bring rxn mixture to pH 13 with 2M KOH.

  6. Extract with EtOAc (3 x 20 mL).

  7. Wash with water (2 x 20 mL) and brine (2 x 20 mL).

  8. Dry with magnesium sulfate.

  9. Evaporate to give a yellow oil (10/6/16). 

Step 4 Yellow Oil.JPG
Observations and Analysis of Crude Product

Dissolved small amount of product in DCM
Bottom = starting material, Center = cospot, Top = product
Step 4 TLC.JPG
1:1 EtOAc:Hexanes solvent system, silica gel plate, UV visualization
Rf(SM) = 0.1, Rf(Prod) = 0.3
Step 4 TLC Ninhydrin Stain.JPG
1:1 EtOAc:Hexanes solvent system, silica gel plate, ninhydrin visualization
Indicates that there is a component in the product that contains an amine (can be visualized using this system) that is not present in the starting material. 

NMR: 1H-NMR (DMSO, 500MHz), 13C-NMR (DMSO, 126 MHz) measured in ppm
NMR for starting material, 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one, can be found in Synthesis of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one (EVKCN 1-3).
1H-NMR of crude product
Product 4 4.jpeg
Product 4 1.jpeg
Product 4 2.jpeg
Product 4 3.jpeg
∂ 8.89 (t, 3H), 8.07 (s, 3H), 7.42 (d, 4H), 7.29 (dd, 3H), 6.91 (dd, 3H), 5.50 (s, 1H), 4.08 (s, 3H), 4.06 (s, 1H), 3.93 (s, 3H), 3.75 (s, 3H), 3.60 (m, 3H) 
13C-NMR of crude product
∂ 65.85
Conclusions and Next Steps
     The analysis of our product indicates that the reductive amination did not proceed successfully. Although the ninhydrin stain indicated the presence of an amine, NMR strongly indicates that it is not our desired product as there are no peaks characteristic in 1H- or 13C-NMR of N-benzyl-1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-amine. In fact, NMR results indicate that the product we isolated may primarily be the alcohol resulting from reduction of the ketone in 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one. Additionally, the aromatic peaks we would expect to see in 1H-NMR are more indicative of a para-substituted impurity (NMR analysis courtesy of Chase Smith via GitHub). 
    Moving forward, there are several possibilities. If the secondary alcohol was produced, it may be possible to oxidize it back to the ketone using PCC following purification (suggestion courtesy of Mandrake Fernflower via GitHub). Alternatively, the reductive amination could be reattempted using different conditions. Chase Smith (via GitHub) suggested performing the reductive amination using sodium triacetoxyborohydride, acetic acid and dichloroethane instead of the procedure outlined above. Lastly, we could attempt to perform an alternative synthetic route in which we perform an aromatic nucleophilic substitution prior to the reductive amination to eliminate the reactive chlorine group (see alternative synthetic route below). This may help to reduce the probability of producing any para-substituted impurity we may have achieved with this synthesis.

The Burns Alternate Synthesis.png

Attached Files
Step 4 TLC Ninhydrin Stain.JPG
Step 4 Yellow Oil.JPG
Step 4 TLC.JPG
Product 4 4.jpeg
Product 4 1.jpeg
Product 4 2.jpeg
Product 4 3.jpeg