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09-06-2016, First step in synthesis of the hetero-oxadiazole, reaction of 2-6 dichloropyrazine with malononitrile, following procedure from Nikishkin et al (2013)
09-11-2016, Work up of the second attempt at step 1
09-23-2016. Step 1 redo, on 5 gram scale
09-24-2016. Work up of 09-23-2016
09-29-2016, work up and purification of [4]
09/28/2016 Step 4, on a larger scale this time. Conversion of methyl 6-chloropyrazine-2-carboxylate [3] to methyl 6-hydrazineylpyrazine-2-carboxylate [4] using hydrazine according to AEW 85-5
10/07/2016 GC mass spec characterization of rxn from [4]->[5]
10/18/16: Trial work up of reaction of 6-chloropyrazinecarbonitrile and hydrazine
10/4/16: Trial of Step 4:Product [4] to Product [5]
10/6/16: Trial Synthesis of 6-hydrazinelypyrazine-2-carbonitrile and from 6- hydrazinelypyrazine-2-carboximidhydrazide from chloropyrazinecarbonitrile
9/12/16 Step 2 in synthesis. Going from [2]->[3]
9/13/16: Work-up of product [3] and TLC plates
9/15/16: Second Synthesis of Methyl 6-chloropyrazine-2-carboxylate [product 3]
9/18/16-9/20/16: Trial Synthesis of Methyl 6-hydrazineylpyrazine-2-carboxylate (Product 4)
9/22/16: Inconclusive Trial Synthesis of Methyl 6-hydrazineylpyrazine-2-carboxylate (Product 4)
9/25/16-9/27/16: Synthesis of Product 3, methyl 6-chloropyrazine-2-carboxylate
9/27/2016 Late Night
9/29/2016 HNMR of product 4, and HNMR of product 4 after D2O exchange 01/10/2016
9/8/16-Continued Synthesis of 2-(6-chloropyrazin-2(1H)-ylidene)malononitrile
CNMR so far
HNMR so far, of all relevant compounds
The Synthetic scheme of Hetero-oxadiazole Synthesis
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20th October 2016 @ 19:10

CNMR data were taken along the way as we reacted, and are shown here.


CNMR of starting material [1] is taken in CDCl3, two peaks are seen and can be assigned to the aromatic carbons, one more downfield than the other due to a bond to Cl. There are two impurities

Screen Shot 2016-10-20 at 3.10.11 PM.png

CNMR of product [2], there were fewer peaks than expected, but we were able to find a peak D in the nitrile range, which indicates the proper product was made. In the future, a greater number of scans in the NMR protocol will be needed to resolve a better spectrum with a complete set of peaks. Due to incomplete set of peaks, accurate assignment of all peaks was not possible

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CNMR of product [3], excellent resolution, we are very excited that peaks E and F indicate successful synthesis of a methyl ester

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CNMR of product [4] had especially low resolution, but we were able to see peaks E and F again, indicating that the hydrazine reaction did not effect the methyl ester moiety as we had feared it might. We could not successfully identify all of the aromatic carbons, and this experiment needs to be repeted with more scans taken in the NMR protocol.

Screen Shot 2016-10-20 at 3.10.36 PM.png


Attached Files
20th October 2016 @ 19:06


The solution from 10/6/16 contained a red liquid and an orange precipitate. Vacuum filtration was used to separate the mixture; it was poured into a Buchner funnel, and washed with ethanol. The precipitate was a flaky orange solid. The weight of the solid was 0.165 grams. From TLC, (TLC plate called orangesolid) it looked like the solid was ones single polar molecule. The eluent was 100% ethyl acetate. Lane 1 was spotted with the starting material, 6-chloropyrazinecarbonitrile, lane 2 was a co-spot, and lane 3 was spotted with the orange solid in methanol. The rf for the starting material was .70, but the orange solid did not move at all on the plate. However, the TLC does show that the starting material was completely used in the reaction, which is promising. When we tried to evaluate the product with NMR, it was not clean (see NMR trace: Foks) There was a DMSO peak at 2.48 ppm, and a large water peak at 3.33 ppm. We believe some of the upfield peaks are ethanol. There were 4 peaks in the aromatic range that all integrate to about ~1. This would make sense if the reaction did make a mixture of products (see scheme 3).

TLC was conducted for the filtrate (TLC plate: filtrate). The eluent was 2:1 ethyl acetate to hexanes. Lane 1: 6-chloropyrazinecarbonitrile, Lane 2: co-spot, Lane 3: filtrate solution. It showed us that there was a mixture of products in the filtrate, but that again, all the starting material was used up in the reaction. We hoped that once we worked-up the reaction, we could isolate a single product.

The work-up of the reaction that we based this scheme on from Folks et. al. included a continuous extraction with ether for 48 hours. Instead, we extracted the filtrate with ether three times with 20 mL. The ether solution was a dull, opaque, yellow-orange color. The volatiles were removed under pressure to leave a red oil (see picture: red_oil). Although we hoped to see one product through TLC, we saw a smudge again. We tried a variety of eluents to try to resolve the products in the oil, but none were successful. The TLC plate attached, called “after_ether,” shows 6-chloropyrazinecarbonitrile in lane 1, a co-spot in lane 2, and a red oil in lane 3. The eluent was 100% ethyl acetate.

Although we could not isolate a single product from this reaction, it would be interesting to see if we carried through the next step (2.2) in scheme 2, if the mixture of products would become product 3.2.

Foks, H. et. al. (1974) Pyrazine derivatives. III. Synthesis and tuberculostatic activity of 6-(N-methylamino)-pyrazine-2-carboxylic acid derivatives Polish journal of pharmacology and pharmacy. 26(5). 537-543.

Attached Files
20th October 2016 @ 18:46

The first steps in our proposed synthesis are very time consuming (See scheme 1). Also, our reaction that turns product 3 into product 4 had a very low yield (1.8%). Therefore, we began to experiment a new way to get to product 4 (See scheme 2). We based our new synthesis on an article by Foks. et al (see attachment Foks_scheme). Although we did not want to copy their synthesis exactly, we think that their chemistry could be mirrored with different reagents in efforts to create product 4. This entry details our trial of step 1.2 in scheme 2 (see attached file: scheme 3). We are not positive what the products of this reaction will be, but in scheme 3 we illustrate 2 probable ones. 



In a 50 mL round-bottom flask, 0.56 grams of 6-chloropyrazinecarbonitrile (MW 139g/mol, 4.01 mmol) was combined with 7 mL of ethanol. 10 mL hydrazine hydrate (~80% in H2O) was added to the round-bottom flask. The solution started off clear, then turned yellow, then subsequently red. The solution was refluxed for 5 hours. After, the round bottom flask was covered with parafilm and left in the hood.

Foks, H. et. al. (1974) Pyrazine derivatives. III. Synthesis and tuberculostatic activity of 6-(N-methylamino)-pyrazine-2-carboxylic acid derivatives Polish journal of pharmacology and pharmacy. 26(5). 537-543.

Attached Files
20th October 2016 @ 15:50

Perfrmed GC mass spec to see if the rxn from [4] to [5] prodcued any appreciable ammout of desired product. Recall that we were unable to isolate the percipitate from this reaction, so we were doubtful that we had any product, however TLC of the reaction mixture showed a mixture that could potentially include our product.


GC of the mixture showed 3 peaks, at 5.92, 13.43, and 14.44.

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Analysis of the 5.92 peak showed a molecular ion peak of m/z=172.0509, which corresponds to unreacted aldehyde 4-(difluoromethoxy)benzaldehyde.

Screen Shot 2016-10-20 at 12.02.33 PM.png


Analysis of the 13.43 peak showed a major peak corresponding to product [4] with mass of 168.9949, and although there were many peaks out past 300, none of them were very tall, they were all minor in concentration

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Lastly, analysis of the 14.44 peak showed nothing around 320 at all, which is where we would expect to see product [5]

Screen Shot 2016-10-20 at 12.02.47 PM.png

This GC mass spec analysis indicates to us that we did not successfully isolate product 5. We hypothesize that it was a percipitate that became stuck in our filter paper due to small quantity. We reccomend next time doing this experiment, starting with a large sample of product [4], at least 10x how much we started with.

Attached Files
6th October 2016 @ 16:51

HNMR was taken of product 4. Product 4 was dried over high vac and was in the flask as a very thin layer of crust, so it was nearly impossible to scrape out. A sample for NMR was taken by pipetting in 0.5 mL CDCl3, dissolving produt 4 from the flask, then pipetting that into a vial and adding an additional 0.5 mL CDCl3. 

HNMR was taken

 and irregularities were noted: notably, contaimation with EtOAc, the aromatic protons giving 3 signals instead of 2, and the NH protons not integrating for 3 protons. 

To attempt to resolve this, a proton exchange was performed with 2 drops D2O and shaking the NMR sample.  

After this shake, the NH protons dissappeared as expected, proving that the peaks initially assigned were correct. We still had the 3 signals for the aromatic protons, but because we had such an excellent 3:1 ratio of those protons to the methyl ester proton, we decided that the spectrum was clean enough to continue. Note that a new peak grows in in the D2O shake spectrum, but we jusge it to be insegnificant because it only grows in after the D2O is added, which only occured in that one vial.
Attached Files