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7th October 2016 @ 20:16

10/7/16

 

A TLC of the pre-workup product was taken to determine if any product had been made. Silica gel TLC was run using a solvent system of 1:1 EtOAc:hexanes and visualized with UV, and can be seen below. Spotted from left to right is the starting material (2.1.4), a co-spot, and the pre-workup product. As can be seen product was made, and while some starting material was present, due to time constraints the work up was carried out even though the reaction had not run to completion.



Work Up:


A saturated aqueous solution of NaHCO3 was added to the reaction mixture until it was basic (tested using litmus paper) The reaction mixture then had 20 ml DCM added to it to determine whether top or bottom layer would be the organic layer (since ethanol is less dense than water but DCM is more dense than water). The reaction mixture was  then extracted with DCM (3 x 100 mL), washed with brine (3x100ml), dried (MgSO4), and concentrated under reduced pressure to give the crude product which was a brown oil.


A TLC was run on the post work-up crude product on a silica gel plate using a solvent system of 1:1 EtOAc:hexanes and visualized with UV, and can be seen below. Spotted left to right is the starting material (2.1.4), a co-spot, and the post-workup product. Starting material is still present and so the crude product will be purified by flash chromatography at a later date.




The crude product was weighed and found to have a mass of 1.7922 g (9.04 mMol), giving a crude yield of 237%.

 

An NMR was taken and can be seen below:



The three peaks integrating for 1 H around 9 ppm indicated the presence of the pyrazine protons, and other peaks around 7 ppm and 4 ppm indicated the presence of the remaining protons on the desired product (5 aromatic protons which should all be around 7 ppm and the two protons next to the carbonyl that should be at about 4 ppm). However, the peaks around 7 and 4 ppm did not integrate cleanly, and the spectrum was filled with other unexplained peaks of drasticly contrasting integration, possibly suggesting the presence of a considerable amount of ethyl acetate and likely other contaminants.


With the NMR suggesting the presence of desired product, but not confirming definitely, a GC-MS was run on samples of the crude product of 2.2 and on 2.1.4 (to see if the starting material for 2.2 was indeed still present in the crude product of 2.2). The GC-MS results for 2.2 and 2.1.4 are shown below:



2.1.4 GC-MS:


Due to the unstable nature of the product of 2.1.4, no peaks were found corresponding to 270.3, the molar mass of the product of 2.1.4. Due to the abundance of fragment peaks though, it is likely that the GC-MS still indicates the presence of 2.1.4 due to the product breaking down in the GC-MS. Since presence of 2.1.4 desired product was already confirmed by proton NMR and due to time constraints, the GC-MS spectrum for 2.1.4 will be analyzed more in depth at a later date. A GC-MS was originally taken of it to reference when looking at the GC-MS of 2.2 to see if much 2.1.4 was still present there. Since no obvious peak in the MS indicates 2.1.4, the spectrum is not immediately helpful in analyzing the GC-MS for 2.2, since (explained below), 2.2 desired product is immediately indicated by its GC-MS so knowing what the impurities are in the 2.2 crude product is not of vital significance now due to the time constraints.



2.2.1 GC-MS:


Due to the jumbled and chaotic peaks of the 2.2 NMR, a GC-MS was run on its crude product to determine for certain if 2.2 desired product was present. The desired product of 2.2 has a molar mass of 198.23 g/mol, and indeed the GC-MS shows a strong peak at 198, indicating the presence of 2.2 desired product.


10/17/16


Knowing that desired product for 2.2 is indeed present, a biotage flash chromatography column was run. Another TLC was taken, spotting a silica gel plate left to right with the starting material (2.1.4), a co-spot, and 2.2 crude product. A solvent system of 2:1 Hexanes:EtOAC was used and the plate was visualized with UV-vis. The TLC can be seen below:



The highest spots in the co-spot and product lanes was thought to ethyl phenylacetate which in previous TLC had been very high up on the plate and was used as a starting material in 2.1.4. The reason for the appearance of multiple spots around the rf of the starting material was unclear, but the product was assumed to be the lowest of the spots in the product lane.


A biotage column was then run according to the TLC above, with the results shown in the image below:



With it unclear which peak corresponded to the desired product, all of the fractions were collected and run in the GC-MS instrument to determine which, if any, contained our purified desired product for 2.2.


10/20/16:

 

 

As can be seen in the above GC-MS spectra, only blue had any peaks from the GC, and the MS for it revealed a fragment with a mass of 197, matching our desired product for 2.2.

 

The blue peak fractions from the biotage were therefore evaporated and found to have a mass of 0.0255 g, giving a yield of 2.9%.

6th October 2016 @ 19:39

10/6//16



The product of 2.1.4 (3.8112 mMol, 1.0301 g) was dissolved in 60 ml ethanol (60% aqueous) containing conc. HCl (20%, 7.6 ml, 18.4 mMol) was heated at reflux (100 oC) overnight.

The solution turned a dark brown color overnight.

Reagents

 

Molar Mass (g/mol)

Mass (g)

mMol

Density (g/ml)

Volume (ml)

Molarity (mol/L)

Equivalency

Ethyl 3-oxo-2-phenyl-3-(pyrazin-2-yl)propanoate

270.28

1.0301

3.8112

     

1

20% conc. HCl

 

36.46

 

18.4

 

7.6

12.1 / 5 =

2.42

4.8

Ethanol (60% aqueous)

         

60

   

Theoretical

               

2-phenyl-1-(pyrazin-2-yl)ethan-1-one

198.22

0.7555

3.8112

     

1

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6th October 2016 @ 02:32

9/29 - 


A column was run on 1.1.2 using 1:1 EtOAc:hexanes based on TLC taken 9/22/16. Although a column was not run in the procedure that we are following, we decided to run one due to the impure nature of the product indicated by the overly high yield. We were able to determine that there were significant impurities from the NMR analysis of 1.1.2 (analyzed 9/22). The product had a lower Rf than the impurity, as shown in the TLC taken on 9/22, so we expect our product to come off the column second. Both this and the impurities are reflected in the results from the biotage. We expect that our product will be the second green peak, while our major impurity will be in the first blue peak. We saved our samples and plan to rotovap and TLC next week.



An NMR in DMSO was taken for both the green and blue samples. They can be seen below:


Green Peak Sample:



The above NMR indicates that some desired product was indeed synthesized, but with impurities still present after the column. The desired product is indicated by the peak integrating for 3H at 4.06 ppm matching the methyl group, and the two doublets integrating for 1H at about 8.75 ppm and the singlet integrating for 1H at 9.33 ppm matching pyrazine protons. The mess of peaks from 7.26-8.08 ppm indicate impurities present as they don’t correlate to any protons in the desired product. These protons are attributed to the continued presence of the starting material mCPBA as this would explain the presence of additional aromatic protons in the spectrum.


Blue Peak Sample:



The above NMR indicates that no product was present in the blue sample as the peaks do not correspond to protons present in the desired product. The three peaks from 7.5-7.8 ppm are too upfield and have the wrong coupling patterns to be the protons in the pyrazine ring, and there is no peak that fits the methyl protons. The presence of aromatic protons in this sample, which according to TLC contains the impurities, further supports that the aromatic proton peaks in the NMR of the green sample are due to impurities still present in the product after the column.


After the flash chromatography purification, only sufficient product was isolated to run the NMR. We therefore have no product to move forward with, and will likely put Scheme 1 on hold in order to try and make more headway in Scheme 2.

4th October 2016 @ 15:46

10/3/16

 

After the successful synthesis of crude product and its unfortunate loss during purification by flash chromatography in the biotage in 2.1.2, and the inability to get product in 2.1.3, Scheme 1 Step 1 was repeated for the fourth time.


Phenyl ethyl acetate (2.75 mL, 0.0173 mol) and methyl pyrazine-2 -carboxylate (1.9900 g, 0.0144 mol) in dry THF (15 mL) were added dropwise with stirring into a freshly prepared solution of sodium ethoxide (0.0173 mol, 1.18 g) in 6 mL ethanol. The solution turned orange and then darkened during the course of the addition. It was heated to reflux for 3 hours (Precedent is Collot et al. JOC Article. 2008, 74, 3368).


Reagent

 

Molar Mass (g/mol)

Mass (g)

mMol

Density (g/ml)

Volume (ml)

Equivalency

Methyl 2-pyrazinecarboxylate

138.12

1.9900

14.4

   

1

Ethyl 2phenylacetate

Image result for ethyl 2-phenylacetate

164.20

2.84

17.3

1.03

2.75

1.2

Sodium Ethoxide

NaOEt

68.05

1.18

17.3

   

1.2

Ethanol

         

6

 

THF

         

15

 

Product:

   

(Theoretical)

(Theoretical)

     

Ethyl 3-oxo-2-phenyl-3-(pyrazin-2-yl)propanoate

270.28

3.89

14.4

   

1




A silica gel TLC of the product was taken using a 1:1 EtOAc:hexanes solvent system and visualized by UV. It was spotted from left to right with ethyl phenylacetate, methyl 2 pyrazinecarboxylate, a co-spot, and what was present at the end of the reflux. The TLC shown below indicates that product had been produced.

Workup -

A workup was then performed as follows. The product of 2.1.3 was poured into 100mL cool water. Unreacted starting material was extracted with 3x50 ml chloroform. These chloroform extractions were set aside to determine if any product was present with TLC. The solution was acidified with concentrated sulfuric acid.The product, now in the organic layer, was extracted with chloroform (3x50mL). A TLC was then taken of the two separate extractions (the first of which should contain only starting materials and the second of which should contain only product).


The TLC was taken on a silica plate in 1:1 Hexanes:EtOAc and visualized with UV-Vis. The spots left to right were starting material, product of 2.1.4 pre-work up, a co-spot, extracts of starting material, and two dots of extracts of product. As can be seen, only the extracts that should have contained product contained product (as compared to the pre-workup). Additionally, the post-workup product did not contain the impurities that the pre-workup product did, showing that the workup was successful.

The product was dried with magnesium sulfate, filtered, and evaporated to give a brown semi-solid.


An NMR of the product was run in CDCL3 and can be seen below:





This NMR indicates that while product is present so are many impurities, likely remaining ethyl phenyl acetate. A peak integrating for 6H at 1.21 ppm matches the methyl protons of the desired product, the peaks integrating for 4H at 4.20 ppm match the two protons adjacent to the CH3 group, the peak integrating for about 1 at 3.6 ppm matches the proton between the carbonyls, and the peaks integrating for about 10H at around 7.3 ppm match the 5 phenyl protons. While the integration of the peaks is often twice what would be expected, this could be explained if there was still ethyl phenyl acetate (which was used in excess)  present which has protons that also have shifts at 1.21, 4.20, and 3.60 ppm, accounting for the double integration at those positions. The presence of ethyl phenyl acetate is further evidenced by the presence of a peak integrating for about 2H at 3.7 ppm which matches its structure. What the desired product has which ethyl phenyl acetate does not are the pyrazine protons, which appear at 8.64, 8.75, and 9.33 ppm as expected and all inetgrate cleanly for 1H, indicating the presence of product. The peak at 2.15 ppm is simply residual acetone.


The actual yield of product was 1.385 g, which when compared to the theoretical yield of 3.89 g gives a yield percentage of 35.6%.

29th September 2016 @ 19:29

9/28/16

 

After the successful synthesis of crude product and its unfortunate loss during purification by flash chromatography in the biotage, Scheme 1 Step 1 was repeated for the third time.

 



Reagent

 

Molar Mass (g/mol)

Mass (g)

mMol

Density (g/ml)

Volume (ml)

Equivalency

Methyl 2-pyrazinecarboxylate

138.12

2.0593

14.9

   

1

Ethyl 2phenylacetate

Image result for ethyl 2-phenylacetate

164.20

2.94

17.9

1.03

2.85

1.2

Sodium Ethoxide

NaOEt

68.05

1.22

17.9

   

1.2

Ethanol

         

6

 

THF

         

15

 

Product:

   

(Theoretical)

(Theoretical)

     

Ethyl 3-oxo-2-phenyl-3-(pyrazin-2-yl)propanoate

270.28

 4.03 14.9     

1

 

Phenyl ethyl acetate (2.85 mL, 0.0179 mol) and methyl pyrazine-2 -carboxylate (2.0593 g, 0.0149 mol) in dry THF (15 mL) were added dropwise with stirring into a freshly prepared solution of sodium ethoxide (0.0179 mol, 1.22 g) in 6 mL ethanol. The solution turned orange and then darkened during the course of the addition. It was heated to reflux for 3 hours (Precedent is Collot et al. JOC Article. 2008, 74, 3368).

TLC run on silica gel plate with a solvent system of 1:1 EtOAc and hexanes visualized with UV showed no product had been made for reasons unclear.
The TLC can be seen below, with starting materials methyl-2-pyrazinecarboxylate and ethyl-2-phenylacetate, a co spot, and product spotted left to right across the plate.
While their is a spot in the product lane, it corresponds to a spot in methyl-2-pyrazinecarboxylate and previous TLC of this step when NMR indicated crude product had been made showed a spot much higher up in the product lane which is absent here. 

This synthesis will be repeated in the hopes of getting desired product.